Major Catalogue Complet

PROJECT SYNOPSES
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EUROPEAN COMMISSION Directorate-General for Research Directorate F Health Unit F.2 Major Diseases Contact: Alain Vanvossel European Commission Office CDMA 2/22 B-1049 Brussels Tel. (32-2) 29 62 578 Fax (32-2) 29 55 365 E-mail: alain.van-vossel@cec.eu.int
EUROPEAN COMMISSION
Major Diseases Research

Catalogue of Research Projects (2003-2005) in the Sixth Framework Programme
Edited by Alain Vanvossel
2005
Directorate-General for Research Life Sciences, Genomics and Biotechnology for Health
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Table of contents
Foreword Introduction Overarching projects

Eicosanox ECRIN-RKP
7 9 11
12 14
Cardiovascular
Bloodomics EVGN MOLSTROKE EuroClot Myocardial Repair
17
18 20 24 26 28
Diabetes
Diabesity EXGENESIS EUGENE2 TONECA IMMIDIAB
31
32 34 36 39 41
Rare diseases
Eumitocombat Euroglycanet GENESKIN EuroWilson PWS EUGINDAT EURAPS AUTOROME Orphanplatform
43
44 47 49 52 56 58 60 62 64
Major Diseases Research (2003-2005)
Anti-Microbial Drug Resistance

EUR-INTAFAR ActinoGEN VIRGIL PNEUMOPEP AMIS PREVIS COBRA micro-MATRIX
67
68 70 73 75 77 79 82 85
Brain, neurological and psychiatric diseases

PROMEMORIA NEWMOOD APOPIS GENADDICT EUROSCA NeuroNE BrainNetEurope II AUTISM MOLGEN SYNSCAFF EUROHEAD SPASTICMODELS NCL-models NEUROKCNQPATHIES X-ALD PainGenes GRIPANNT STRESSPROTECT INTERDEVO NeuroDisseminator EUROMEMO ESNI course 2003 FENS Forum 2004 RABRE
87
88 90 93 95 97 100 102 106 108 111 113 116 118 120 122 124 126 129 131 132 135 137 139
Human development and ageing

MIMAGE GEHA EMBIC Cells into Organs
141
142 144 146 148
LINK-AGE ANABONOS OSTEOGENE AGEACTION
150 152 154 156
Cancer
INTACT BIOCARE Angiotargeting PRIMA Active p53 EMIL TRANSFOG FIRST CANCERDEGRADOME STROMA Mutp53 MOL CANCER MED EUROXY MAESTRO CCPRB eTUMOUR TRANSBIG European LeukaemiaNet DNA METHYLATION European MCL Network BRECOSM MetaBre ENACT PROTHETS P-MARK EUSTIR EUROCAN +PLUS
159
162 164 166 168 170 173 176 179 182 185 187 191 194 195 196 198 200 202 206 209 212 214 217 219 221 223 225
Indexes
Index by acronym Index by contract number Index by project coordinator
227
228 230 232
Foreword
Millions of European citizens battle with chronic diseases every day. The ultimate objective of any health research funding is to eliminate such diseases. The task is huge - major diseases,such as cardiovascular,brain diseases and cancer,are immensely complex and can often only be tackled by multidisciplinary teams from different countries.For over a quarter of a century,European Union Framework Programmes have supported research in life sciences,providing opportunities for research funding and the training of scientists. Europe is fortunate to have excellent research centres active in these fields the challenge is to ensure their further development and to facilitate the creation of effective and durable partnerships between them. The current Sixth Framework Programme focuses on major diseases as part of its first thematic priority 'Life sciences, genomics and biotechnology for health', with an emphasis on the field of genomics which has ushered in a new era in medical research. This publication illustrates the EU's essential commitment to major disease research, featuring the 87 projects supported under the first and second calls for proposals in the actual Framework Programme, representing a global budgetary effort of about 380 million. Let us not underestimate this collaborative research effort, bringing together the best teams in Europe in basic research,molecular biology,clinical expertise,epidemiology and bioinformatics.It must be recognised that,through the research Framework Programmes,the EU has the largest experience in the world thanks to such multinational and multidisciplinary co-operation which is essential because of the scale of the problems faced. These multiskilled approaches are needed to generate important advances in our scientific knowledge and ultimately to lead us towards new drugs, therapies and treatments for the benefit of the patients and for public health in general. Research must become embedded in healthcare. As sure as research delivers solutions to some problems, it also opens up further questions.The current work being funded should also help to point us in the right direction as we prepare for the Seventh Framework Programme, now expected to embrace even broader ambitions and objectives for co-operation in health research. As Commissioner for Research, I am convinced that increased support in (health) research is a key element for Europe's industrial growth and a cornerstone of the knowledge based economy and society.
Janez Potocnik
Introduction
The current Sixth Framework Programme (FP6 20022006) is dedicating around 800 million to supporting research in the area of 'Combating major diseases: application-orientated genomic approaches to medical knowledge and technologies' with the aim of improving patient health and quality of life in Europe and around the world. Under FP6,five possible funding instruments provide support to larger or smaller projects with different objectives. Integrated Projects (IP) and Specific Targeted Research Projects (STREP) are aimed at generating, demonstrating and validating new knowledge through research and development. Networks of Excellence (NoE) support strategic research coordination through extensive networking. Coordination Actions (CA) and Specific Support Actions (SSA) promote collaboration and coordination of smaller scale projects,and other activities such as conferences and studies. Collaboration between industry and academia is strongly encouraged. Emphasis is placed on the participation of small and medium-sized enterprises (SMEs) in all FP6 initiatives, including this part of the programme, in recognition of their important and proven innovative potential. This catalogue features 87 projects selected under the first and second FP6 calls for proposals, presented by scientific area, for a total contribution of about 380 million provided by the EU. Several excellent projects have incorporated innovative post-genomic and proteomics approaches.They are identifying genes,collecting data and applying innovative bioinformatics techniques including the use of model organisms to elucidate cellular and molecular mechanisms, and to elaborate clinical aspects of diseases with a strong potential for new diagnostics. This part of the FP6 thematic priority 'Life sciences, genomics and biotechnology for health' (TP1) covers a large spectrum of major diseases and, as such, supports research to combat cardiovascular diseases, diabetes and rare diseases; tackles the problem of antimicrobial drug resistance; studies the brain and neurological and psychiatric diseases; enhances knowledge about molecular mechanisms of human development and healthy ageing; and finally, combats cancer. Cardiovascular diseases claim more lives in Europe than any other medical condition.The World Health Organisation estimates that they cause some 30% of mortality worldwide.Despite the growing number of interventional and pharmacological approaches, much remains to be done. Some of the main aspects of cardiovascular diseases have already been addressed by the first two FP6 calls for proposals,namely coronary artery disease, vascular diseases, atherothrombosis and thrombotic stroke, heart failure, arrhythmias and myocardial repair. Europe has seen an explosive increase in diabetes over the past two decades.Today, an estimated 20 million people in the EU (about 4% of the population) suffer from this debilitating disease, excluding undiagnosed cases.This figure is expected to grow to at least 26 million by 2030. Diabetes lowers the life expectancy of sufferers by up to 15 years and increases the risk of cardiovascular disease by two to four times. Projects funded under the first two FP6 calls for proposals are tackling the prediction of type 1 diabetes while, with respect to type 2 diabetes (TP2D), projects are addressing the treatment of obesity, the effects of exercise and the genetics of TP2D in migrant population. 'Rare diseases' (RDs), by definition, affect only small groups of people. In Europe, RDs are defined as those affecting less than one person in 2 000.These conditions are often genetic in nature, usually severely debilitating and life-threatening.Their low prevalence,the only feature shared by all RDs, confirms the undeniable added value of teamwork and pooling of resources and patient data at the European level. Rare diseases and disorders covered by the first two calls include disorders of mitochondrial oxidative phosphorylation, glycosylation and plasma membrane amino acids transporters; rare skin diseases; Wilson's disease; Prader-Willi syndrome; and autoimmune diseases. Some projects take a broad approach,addressing personalised medicine and plan for the coordination of early clinical trials. Over time, bacteria, viruses, and other microscopic predators mutate into new strains resistant to existing medications. The problem of resistance to antimicrobials has grown into a major health concern and now threatens to impede advanced medical interventions as well as treatment of common infections. Mortality due to drug resistance has increased, while costs for medical care due to treatment failures have escalated. Some of the major aspects of this problem have already been addressed in the first two calls through projects focusing on the design of new antibiotics (addressing new molecular targets) and new alternative treatment approaches (addressing virulence factors and stimulating the immune response), improved understanding of the molecular mechanisms behind antibiotic resistance, and the establishment of a vigilance network to control and predict the development of antiviral drug resistance. The brain may well be the most complex organ in the human body. One-third of our genes and proteins are specific to the brain alone, providing the basis for our unique intellectual capabilities.The more we understand about how the brain works, the more we can unravel the causes of the many devastating neurological and psychiatric disorders and diseases, and try to find new treatments or even cures. Neurodegenerative diseases have been tackled on a broad scale under the first two calls for proposals. Two large initiatives, an IP and a NoE, are addressing all related disorders displaying abnormal protein aggregation, including Alzheimer's, Parkinson's and Huntington's diseases, motor neurone diseases and prion diseases.The NoE on 'Human brain tissue research' is addressing brain banking. One project covers a rare genetic neurological disorder, spinocerebral ataxia, which causes progressive movement disorders.
Important funded research projects in areas such as affective disorders, mechanisms of addiction or mechanisms of learning and memory, migraine and pain in general, are now expected to generate major impacts through the use of recently available genome data. Other projects cover drug development related to cytoprotection and inhibition of stress. Growing old is a normal part of life, but it brings its own particular health challenges with it. The EU seeks to help Member States encourage good health for European citizens from the cradle to old age as the ranks of the 'silver generation' grow, addressing their specific medical needs will become ever more important.The area of 'human development and ageing' is meant to provide a strong knowledge base for medical needs and good health throughout a patient's lifetime.The study of healthy ageing has been addressed by the first two FP6 calls, specifically with respect to genetic aspects and the role of mitochondria. One NoE and one IP, addressing the development of organs and embryo-implantation, respectively, tackle questions of human development. Bone formation, anabolism and osteoporosis are also covered. Cancer is likely to remain one of the biggest killers of the beginning of the 21st century. In Europe, almost 1 million people die of cancer every year, and 2 million new cases of cancer are diagnosed. Cancer is an elusive enemy. Its multiple causes including genetic predisposition, environmental and life-style influences, infectious agents and ageing and their complex interactions represent a major challenge for basic and clinical research. So far, the budget allocated specifically to the calls in the 'Combating cancer' section has enabled the funding of 27 projects. A number of these focus on the analysis of molecular targets, such as cell-cycle regulators, kinases, phosphatases, telomerase, proteases, DNA repair molecules, p53 protein, and mitogen-activated protein kinase (MAPK) signalling, and on molecular mechanisms surrounding angiogenesis, epigenetics and hypoxia. Research is also being funded on biomarkers for early detection, prognosis and responsiveness to treatment.Moreover,therapies,such as viral therapy, stem cell therapy, gene therapy, radiotherapy, novel technologies, together with the development of new drugs, are being covered by the funded projects. In addition, research on molecular imaging is being supported by EU funding.There are also a number of studies specific to particular types of cancer, such as leukaemia, lymphoma, myeloid cell leukaemia, melanoma, colon cancer, breast cancer, pancreatic cancer, prostate and childhood cancers. Finally, one large IP has been funded on the topic of functional genomics and proteomics of the pathways of nitric oxide and eicosanoid signalling and their interactions.This initiative is overarching several diseases, ultimately aiming to develop new therapies and treatments for cardiovascular, cerebral and neoplastic diseases. As can be seen from the catalogue, these 87 projects represent a massive effort from the EU scientific community involved in life sciences research for the ultimate benefit of both the patient and the European citizen.
Acknowledgment
This catalogue has been produced thanks to essential input from all project coordinators involved and the efficient co-operation of all members of Unit F2 'major diseases', in particular Catherine Berens, Philippe Cupers, Dambrauskaite Virginija, Mary Fitzgerald, Olaf Kelm, Elengo Manoussaki, Elmar Nimmesgern, Jrgen Sautter, Nathalie Vercruysse, Jan Van de Loo, Maria Vidal, Christian Wimmer, all under the inspiring coordination of Thomas Jussen and Ludovica Serafini and the guidance of Alain Vanvossel.
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Overarching projects
Eicosanox ECRIN-RKP 12 14
OVERARCHING PROJECTS
Eicosanox
Eicosanoids and nitric oxide: Mediators of cardiovascular, cerebral & neoplastic diseases
Summary
The eicosanoids and nitric oxide (NO) are important signalling molecules in many physiological and pathological processes, including cardiovascular, cerebral and neoplastic disorders. Together, these diseases account for the vast majority of deaths in Europe and represent an enormous health problem with a major socio-economic impact. We have assembled a large consortium, positioned at the forefront of eicosanoid and NO research. The partners will carry out a multidisciplinary project, aiming to increase the knowledge of these autacoids, and to develop novel therapeutic strategies and medical treatments. We will carry out molecular studies on key enzymes and receptors to elucidate biochemical properties, catalytic mechanisms and structure-function relationships. We will address the functional genomics of the Eicosanoid and NO cascades to characterise gene expression profiles and regulation under normal and disease states, and identify novel potential drug targets. New genes will be characterised using proteomics, structural genomics and model organisms. In parallel, the partners will conduct cell biological work on gene regulation, gene silencing, signalling systems and cross-talk between pathways. This information will be used in studies of disease mechanisms such as inflammation, immune responses and angiogenesis. In turn, these insights in pathology will be translated into investigations of diseases using animal models and clinical applications. The basic research together with applied and clinical studies will act in synergy to identify novel targets for pharmacological intervention and drug design for the treatment of patients suffering from cardiovascular, cerebral and neoplastic disorders.
Problem
Eicosanoids and NO are involved in a number of severe endemic diseases that plague the Western world, e.g.atherosclerosis,myocardial infarction, thrombosis, dementia and cancer. In fact, cardio- and cerebrovascular disorders alone, such as coronary heart disease and stroke, are the leading cause of death in Europe.Together with cancer, these diseases account for the vast majority of mortality and morbidity among adults in Europe.The project will increase our knowledge of these common and deadly diseases and the mechanisms by which eicosanoids and NO trigger and maintain pathophysiological processes, with the long-term goal of developing novel drugs and therapeutic strategies.
Aim
The projects goal is to generate new knowledge about cardiovascular, cerebral and neoplastic diseases.The work involves basic molecular studies of proteins, investigations of gene regulatory mechanisms, cellular signalling mechanisms and functional genomics and proteomics approaches to identify new genes. In turn, this work will be translated into applied and clinical research activities.Together with evaluations in animal models, clinical patient studies and programmes on drug design,we expect to develop novel therapeutic strategies and medical treatments for several severe diseases. We will also create a longlasting infrastructure for R&D activities, education, training, exploitation and dissemination of results to users at multiple levels, such as research organisations, funding agencies, patient associations, industry, and society in general.
Expected results
It is envisaged that molecular work, including biochemistry, protein chemistry, studies of structure function relationships and enzyme regulation will generate basic knowledge of the molecular properties of the key proteins in the eicosanoid and NO cascades. We will take advantage of the human genome sequence and employ front-line technologies in functional genomics and proteomics
12
research to identify genes that participate in the biological responses elicited by eicosanoids and NO.Thus, we will carry out a large integrated programme on systematic microarray analyses for mRNA profiling of regulated genes in a variety of in vitro and in vivo model systems for disease processes. Using a proteomics approach, new genes will be characterised at molecular and functional level, using an array of biochemical and biophysical methods, structural genomics and model organisms. These joint activities are expected to generate important insights to the regulated expression of genes in the eicosanoid and NO cascades, cross-talk between the pathways, and identification of novel genes involved in the regulation and action of these autocoids, i.e. novel potential drug targets. Along with this work, we will conduct work on cellular regulation of eicosanoid and NO biosynthesis and action, including complementary tasks on gene regulation, gene silencing expression and function of receptors, intracellular signalling mechanisms and cross-talk between pathways. This knowledge will in turn be translated into studies of basic pathophysiological mechanisms, in particular inflammatory and immune reactions, as well as angiogenesis. Insight into the role of eicosanoids and NO in basic pathology will be connected to direct investigations of cardiovascular, cerebral and neoplastic diseases, using animal models and clinical applications on human tissues and patient studies.Thus, the basic research and applied and clinical studies will act in synergy and facilitate efforts to identify novel targets for pharmacological intervention and drug design. These joint efforts will allow development of novel therapeutic strategies and medical treatments for patients suffering from diseases of the cardiovascular and central nervous systems and cancer.
Coordinator
Prof. Haeggstrm, Jesper Z. Division of Chemistry 2 Department of Medical Biochemistry and Biophysics Karolinska Institutet Stockholm, Sweden Phone: +46 8 524 87612 Fax: +46 8 736 0439 Email: jesper.haeggstrom@mbb.ki.se Project web-site: http://www.eicosanox.org Key words: eicosanoids, nitric oxide, cardiovascular disease, brain disease, neoplasia, inflammation, angiogenesis, drug development, therapy, molecular biology, cell biology, genomics, proteomics
Partners
Karolinska Institutet, Sweden University of Frankfurt, Germany Universit degli Studi di Milano, Italy Fondazione Universit Gabriele Dnnunzio, Italy Wolfson Institute for Biomedical Research, United Kingdom Queen Mary & Westfield College, University of London, United Kingdom National University of Ireland, Ireland Nicox Research Institute Srl, Italy Universidad Autonoma de Madrid, Spain Biolipox AB, Sweden Queens University, Canada University Clinics Charit, Humboldt University, Germany
Potential applications
Our project will increase our knowledge about these common and deadly diseases and the mechanisms by which eicosanoids and NO trigger and maintain pathophysiological processes. In addition, we intend to identify new drug targets, evaluate the therapeutic potential of recently developed lead structures, improve existing therapies and develop novel drugs and therapeutic strategies.
Acronym: Eicosanox Project number: LSHM-CT-2004-005033 EC contribution: 10 700 000 Instrument: Integrated Project Duration: 60 months Starting date: 01/01/2005
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ECRIN-RKP
European Clinical Research Infrastructures Network (ECRIN) - Reciprocal Knowledge Programme (RKP)
Summary
Based on the interconnection of national networks of clinical research centres (CRCs) and clinical trial units (CTUs) the European Clinical Research Infrastructures Network (ECRIN) programme is designed to develop an infrastructure allowing for bottom-up harmonisation of support, training, and practice of clinical research. ECRIN aims at providing public or private (mainly biotechnology SME) sponsors with a support for translational research and multicentre clinical studies in Europe.The ECRIN consortium is based on national networks of CRC / CTUs together with the European Forum for Good Clinical Practice (EFGCP).A major objective of ECRIN consists of stimulating and facilitating the creation of centres and national networks,especially in the new member states, for their subsequent connection to the European network. Connecting these national networks within a broad European network will contribute to the critical mass at the European level needed for the implement of European standards and training regarding clinical research. The European Consortium of clinical research infrastructures currently includes eight networks of CRCs and CTUs, covering six European countries representing 260 million citizens (Denmark, France, Germany, Italy, Spain, and Sweden), and comprising 112 different medical centres and hospitals conducting 1500 clinical studies.
Potential outcome
The ECRIN-Infrastructure project will be developed later and will consist of the build-up of an infrastructure facilitating transnational clinical studies and including networking activities allowing for harmonisation of training, tools and practice. Networking activities are designed to promote a harmonised implementation of good clinical practice, according to Directive 2001/20/EC and Member State legislation, a harmonised training and practice in clinical research, and communication with investigators, patients and citizens. Workgroups will cover the impact of national legislation on clinical studies, ethical issues, good clinical practice and harmonisation of SOPs, data management and quality control procedures.Topic-specific subnetworks,collection of biological material, and transnational cohorts will be promoted, while circulation of information will target the main actors of clinical research, i.e., investigators and researchers, scientific associations, the Cochrane Collaboration, funding agencies, and industry partners, as well as patients and patients associations. European Correspondents in each national network will participate in such networking activities. Transnational access activity will facilitate the realisation of multinational studies through a panel of flexible services proposed to the sponsors (however ECRIN will not act as a sponsor by itself). Services provided will rather include consulting for centre selection, funding opportunities, protocol review, ethical review, biostatistics, data and safety monitoring committees, and insurance, whereas support will be provided for regulatory affairs,drug dispensation,data monitoring, pharmacovigilance and management of SAE, and data custody and intellectual property. Transnational access to ECRIN facilities will be delivered, after scientific, methodological and ethical review, through a Co-ordination Team whose role consists of solving problems raised by transnational studies with the help of European Correspondents in each national network. Joint research projects aim at improving the quality of the services delivered by the ECRIN-Infrastructure. This is achieved through a European joint research programme in ethics, informed consent, and gender issues.
Objectives
The ECRIN-RKP project is designed to exchange information regarding the organisation of national networks and their environment. This ECRIN-RKP project is the first step of a wider ECRIN programme designed to build up an infrastructure promoting a harmonised implementation of the EU Directives regarding clinical research, and providing academic or biotechnology sponsors with a support for the conduct of multinational clinical studies/trials in Europe (the ECRIN Infrastructure project). Optimising the ECRIN Infrastructure project requires an in-depth reciprocal knowledge of all partners and of their national environment, leading to refinement of the content of items specific for infrastructure projects, namely the networking activities, the transnational access activities and the joint research projects. Prepared by national workshops, the ECRINRKP action is therefore based on a diagnostic step devoted to a comparative analysis (a workshop in Brussels on 16-17 December 2004, with three representatives per network), followed by a closure meeting (on 14-15 February 2004,in Brussels,with one representative per centre) designed to discuss which points require harmonisation and which services could be proposed for transnational access.
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The project is designed on a progressive growth model of the initial network through the addition of new national networks (with special attention provided to the new Member States),thereby increasing the efficiency of the infrastructure. In addition, this SSA allowed to participate in the preparation of the FP7 Technology Platform 'Innovative Medicines for Europe' (Barcelona workshop). ECRIN also participated in the debate on transparency in clinical trials, and will co-ordinate a communication event on clinical research, targeting EU citizens and patients associations. national multicentre studies alongside the interconnection of skills and logistics. However, some EU countries still lack such networks. 3 - ECRIN network The ECRIN consortium of clinical research infrastructures includes eight networks of clinical research centres (CRCs) and clinical trial units (CTUs), covering all the medical fields. Currently, these networks cover six countries representing 260 million citizens.Therefore they reach the critical mass both at their country level and at the EU level.No equivalent infrastructure exists in Europe. In addition, the Canadian participant (FRSQ-GEREQ) extends the capacity of ECRIN to perform clinical studies on the North American continent, using data management tools compatible with FDA requirements. Closely associated with scientific associations and investigators, acting through disease-specific networks of practitioners, these centres have the capacity to enrol patients in a wide range of clinical studies, particularly in rare diseases, orphan drugs, paediatrics, biotherapy.
Participants
The ECRIN consortium is designed to provide a European not-forprofit platform for the investment and realisation of trans-European clinical research projects. ECRIN is not directed towards a specific speciality or disease category, but will foster transfer of best research practice from speciality to speciality all over Europe. 1 - CRCs and CTUs The development of Clinical Research Centres (CRCs) in Europe occurred in the 1990s in some countries with the support of health or research ministries, of universities, hospitals, and government agencies, and of foundations.Allowing investigation through a team of study nurses, physicians, specific beds and equipment, each centre acts as a facility providing support for research projects, acting through strong connections with physicians from various medical fields involved in the design of the project, in its realisation, and in the enrolment of patients. Clinical research centres also provide expertise for drug registration, and represent a bench-to-bedside link between research laboratories and clinical studies,either through clinical applications of new strategies, or through the investigation of patients for genotype/phenotype, or pathophysiological studies. The concept of Clinical Trial Units (CTUs) developed earlier and has extended in Europe over the past ten years. Not necessarily based in a hospital, their main activities consist in providing specialist knowledge for planning, conducting, and reporting clinical trials (including phase I, phase II, and phase III trials) that may include from several patients to several thousands of patients. Their task includes design of the trials, implementation of the randomisation of the patients, case record form (CRF) development and collection, database building and checking, analysis of the data, and reporting of the results. Their staff includes statisticians, project managers, data managers, and computer engineers. They are closely collaborating with clinicians, supporting them in all the steps of clinical trials. Most of the CTU are also performing other types of clinical studies (diagnostic evaluation for instance) and epidemiological studies. Medical teams participating in the trial may be helped for data collection by study nurses or research assistants, or by CRCs. This illustrates the complementarity between both structures, CTUs often provide CRCs with methodological and data management support.Many CRCs are mainly involved in the early phases of drug and device development, CTUs in later ones. 2 National networks of CRCs/CTUs In most countries,the organisation of the first national networks only appeared recently, permitting critical mass achievement, and leading to the standardisation of practice in these countries, and the facilitation of
Coordinator
Demotes-Mainard, Jacques CIC INSERM-CHU de Bordeaux CHU Haut-Lvque,Avenue de Magellan 33604 PESSAC, France Phone: +33 55765 6170 Fax: +33 55765 6168 Email: demotes@bordeaux.inserm.fr Project web-site: www.ecrin.org Key words: clinical research, infrastructures, harmonisation, transnational studies
Partners
Clinical Research Centres / Clinical Trial Units Network, Denmark Rseau Franais des Centres dInvestigation Clinique INSERM-Hpitaux, France Rseau Franais dunits dessais cliniques, France Netzwerk der Koordinierungszentren fr Klinische Studien, Germany Consorzio Italiano per la Ricerca in Medicina, Italy Istituto Mario Negri. Italy Spanish Clinical Research Network, Spain Clinical Research Centres / Clinical Trial Units Network, Sweden European Forum for Good Clinical Practice
Acronym: ECRIN-RKP Project number: LSHM-CT-2004-511963 EC contribution: 225 000 Instrument: Specific Support Action Duration: 12 months Starting date: 13/05/2004
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Cardiovascular
Bloodomics EVGN MOLSTROKE EuroClot Myocardial Repair 18 20 24 26 28
CARDIOVASCULAR
Bloodomics
Identification of risk genes for atherothrombosis in coronary artery disease by transcriptome and proteome analysis and high throughput exon resequencing
Summary
Coronary artery disease and atherothrombosis cause more deaths in Europe than any other disease.About 600 000 people are diagnosed with myocardial infarction (MI) yearly, with 50% of cases being fatal and many of the survivors experiencing a reduction in quality of life. Early identification of individuals at risk has proven difficult in the past. With state-of-the-art tools and technologies at hand,the Bloodomics project aims at discovering markers associated with a higher risk for arterial thrombus formation and MI. In the post-genome era, the Bloodomics project makes use of the completed human genome sequence as well as employing high throughput platforms for sequencing, genotyping for single nucleotide polymorphisms (SNPs), gene expression analysis, proteomics and RNA interference. Integrating the knowledge generated with these different platforms with clinical information from MI patients will lead to the identification of genetic markers for atherothrombosis. The Bloodomics project focuses on the genetics and cell biology of platelets,since we hypothesise that the response of platelets is critical in determining whether thrombus formation will lead to arterial blood vessel occlusion. Initially, we will identify platelet genes and gene variants that contribute to atherothrombosis. Later we will determine the physiological role of the corresponding proteins and characterise the signalling pathways involved. This comprehensive approach will provide new insights into the causes of coronary artery disease and atherothrombosis, eventually leading to the development of new strategies for prevention and novel anti-platelet drugs for treatment. The Bloodomics consortium has brought together a multi-disciplinary team from 14 world leading academic centres across Europe. Five leading clinical coronary artery disease units,groups specialized in cell biology and signalling, haematopoiesis and proteomics will work together with Europe's premier genome centre in this challenging discovery programme.The programme will be underpinned by a team of ten bioinformaticians and four statisticians. In addition, two young companies,Domantis Ltd,an antibody engineering company and Trium Analysis Online, a company developing online solutions for biostatistics, epidemiology and informatics, will make critical contributions. By adding 30 new positions to the existing 160 staff in the affiliated institutes, Europes commitment to basic and translational research in coronary artery disease and atherothrombosis will be strengthened.
The clinical challenge

The risk of cardiovascular disease is determined by the interplay between an individuals genetic background,lifestyle and environment. Twin studies have clearly demonstrated a genetic component for cardiovascular disease and several risk genes have already been discovered. However, genetic markers to predict the risk of atherothrombosis are currently not available. The absence of such markers means that there is a risk of an excess of preventative treatment. As an example, long-term aspirin use can cause bleeding and its benefits for the population at large become marginal if it is used too widely.
Aim
The Bloodomics project aims to discover genetic markers for the prediction of thrombus formation in coronary artery disease and to design better anti-thrombotics for improved prevention and treatment.
Expected results
During the course of the project, 300 candidate platelet genes that are potentially associated with arterial thrombus formation will be identified using complementary approaches.Three different routes will be used to discover candidate genes. First, we will define the platelet response to several well-characterised agonists in a large group of healthy individuals and then identify differences in mRNA and protein abundance using microarray and proteomics in extreme end samples. Second, we will compare the transcriptome of platelets from MI patients and controls. Finally, we will discover novel genes important for platelet function by studying rare pedigrees with unexplained autosomal recessive bleeding disorders of the platelet type. Based on the common disease-common alleles hypothesis,the genetic variants in the 300 candidate genes will be identified by exon resequencing in a reference panel of 48 individuals.This will lead to the discovery of common alleles.To determine whether certain alleles do confer a statistically significant risk to coronary artery disease or related events, we will analyse the frequency of these polymorphisms in a Phase-I case-control study using the DNA of 2 000 wellcharacterised patients and 2 000 common controls. By this direct approach alleles that may confer a relative risk of at least 1.5 will be discovered.These putative risk genes (predicted to be 5-10% of the initial 300 candidate genes) will require further investigation in a PhaseII case-control study with another 3 000 patients and controls. We will be able to achieve this because the Bloodomics DNA repository provides access to samples and clinical phenotype information from over 10 000 patients with coronary artery disease and 10 000 common controls.
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CARDIOVASCULAR
Structure of the VWF-binding domain of GpIba: Ribbon representation of GpIba.The NH2-terminal hairpin, called finger, is coloured blue; the eight leucine-rich repeats are green.The COOH-terminal flanking region is coloured red and contains a disordered loop (residues 227-241) called switch. Disulfide bridges are indicated in yellow ball-and-stick representation.
Coordinator
Dr.Willem H. Ouwehand European Cardiovascular Genetics Foundation (ECGF), Department of Hematology, University of Cambridge, Long Road Cambridge CB22PT, United Kingdom Phone: +44-1223-548 037 Fax: +44-1223-548 136 E-mail: willem.ouwehand@nbs.nhs.uk Project website: www.bloodomics.org
We will integrate the results obtained in functional and cell signalling studies with the transcriptome, proteome and genetic data of a large number of healthy individuals and patients. It is expected that this will result in a library of platelet functional signatures and genetic fingerprints. This integrated library will be a powerful tool towards personalised medicine in coronary artery disease. Finally, the application of RNA interference in human haematopoietic stem cells will further allow us to gain insight into the function of novel platelet proteins that are discovered within the candidate gene programme. In combination with an antibody production pipeline, it is expected that we may identify novel targets for drug development.
Key words: coronary artery disease, atherothrombosis, myocardial infarction, platelet, RNAi, microarray, proteomics, genotyping, sequencing, case-control study, clinical cohort
Partners
The Chancellor, Master and Scholars of the University of Cambridge, United Kingdom European Cardiovascular Genetics Foundation, Cambridge, United Kingdom Genome Research Ltd/Wellcome Trust Sanger Institute, Hinxton, United Kingdom Universitair Medisch Centrum Utrecht,The Netherlands Academisch Ziekenhuis bij de Universiteit van Amsterdam, The Netherlands Katholieke Universiteit Leuven, Belgium Stichting Sanquin Bloedvoorziening, Amsterdam, The Netherlands LURIC Datenbank Gesellschaft brgerlichen Rechts, Freiburg, Germany Associazione per lo studio della trombosi in cardiologia, Pavia, Italy Trium Analysis Online GmbH, Munich, Germany Medical Research Council/Biostatistics Unit, Cambridge, United Kingdom
Identification of individuals at risk is paramount for an effective preventative health care strategy that aims at reducing the morbidity and mortality of heart disease. Future improvement in coronary care is also dependent on new and safe drugs.The Bloodomics project will make contributions in both of these areas. First, genetic risk markers for atherothrombosis will be discovered. Second, novel targets will be identified and development of anti-thrombotic drugs will be supported by structural studies. Finally, the project will generate population genetics data from large cohorts of patients and controls from different European member states.
Acronym: Bloodomics Project number: LSHM-CT-2004-503485 EC contribution: 8 879 155 Instrument: Integrated Project Duration: 48 months Starting date: 01/06/2004
Domantis Ltd, Cambridge, United Kingdom University of Leicester, United Kingdom University College Dublin, Ireland Subcontracting: National Institute for Biological Standards and Control, Potters Bar, United Kingdom
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EVGN
European Vascular Genomics Network

Summary
Cardiovascular disease (CVD) caused 51% of deaths in Europe in 2001. Coronary heart disease and stroke, which result from atherosclerosis, constitute 80% of CVD. Better prevention and treatments have halved age-specific incidence, but the ageing population and adverse trends in obesity and diabetes threaten these improvements. There is also an alarming increase in heart failure, the end stage of coronary heart disease.Future advances depend on developing entirely new strategies. Genomics and proteomics together open up fresh horizons for 1) endothelial dysfunction, an early critical event in atherosclerosis and hence a target for prevention; 2) plaque instability,responsible for precipitating thrombosis and hence most life-threatening acute events; and 3) therapeutic angiogenesis,either conventional or cell-based to recover ischemic organ function and reduce heart failure. Our research armoury spans genomics,proteomics,molecular biology,cell biology, gene transfer and genetic modification in mice, and integrative pathophysiology in man.The EVGN will maximise the scientific and commercial potential of European vascular biology by electronic data-sharing and communication networks, shared research tools, and exchange and training programmes. The EVGN will train tomorrows lead investigators through a European training programme for PhD students,which will also address adverse gender balance and encourage excellence in eastern Europe, which suffers high prevalence of CVD. molecular understanding of cardiovascular disease, for identifying new diagnostic measurements and developing new pharmacological, gene and cell-based therapies. The European Vascular Genomics Network (EVGN) assembles the necessary critical mass and promotes multidisciplinary interactions by uniting 25 world-leading basic and clinical institutions from nine European countries.It focuses on the three areas with greatest therapeutic potential:
Expression of the adhesion molecule VCAM-I (in brown) by the endothelium of a mouse fed an atherogenic diet for 10 days. Lumen on the right
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Atherosclerotic plaques (in red) at the surface of the aorta from a mouse deficient in apolipoprotein E
Problem
Cardiovascular disease is the leading cause of death in the European Union, accounting for over 1.5 million deaths each year (5 million in Europe). Nearly half (42%) of all deaths in the EU (51% in Europe) in 2001 were from cardiovascular disease, while cancer caused 20%. Ischemic heart disease and stroke, which have a predominant vascular origin resulting from atherosclerosis, account for most deaths from cardiovascular disease (80%). Age-specific incidence rates for cardiovascular disease have fallen by half over the past 30 years in the economically advanced European nations, as the result of better prevention and treatments based on growing knowledge of vascular biology. Although these measures are becoming widely disseminated, an additional dramatic effect on cardiovascular disease incidence and mortality is unlikely to be achieved without the development of entirely new therapeutic and preventive strategies. Recent advances in genomics open new avenues to understand the molecular basis for cardiovascular disease and hence design new diagnostic tests and classes of drugs based on hitherto unknown target genes.Therapeutic approaches including DNA vaccination, gene therapy and cell therapy may revolutionise the prevention and treatment of atherosclerosis. Accordingly, the European Vascular Genomics Network (EVGN) is a timely initiative aimed at maximising the impact of the post-genome era on vascular biology so as to optimise the conversion of research results into concrete health, social and economic benefits.
Aim
1.The EVGN networks and structures the leading European groups already involved in an uncoordinated way in applying genomics to vascular biology research, so as to maximize their potential. The network focuses on the 3 research areas, endothelial dysfunction, unstable atherosclerosis and therapeutic angiogenesis that appear most likely to generate benefits for patients. a) Endothelial dysfunction is an early prognostic marker and important pathological mechanism underlying the development of atherosclerosis.A major goal of the EVGN is to develop new diagnostic tools and means to correct endothelial dysfunction, which could have a major impact on atherosclerosis prevention. b) Potentially fatal myocardial infarctions and strokes are precipitated by acute atherosclerotic plaque instability, either surface erosion or rupture of the fibrous cap.The EVGN is aimed at identifying the genes that mediate plaque instability in humans, designing diagnostic tests to identify high-risk individuals and developing drugs to decrease risk of rupture.
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c) Insufficient neoangiogenesis is an integral component of loss of organ function following chronic ischaemia or acute ischaemic injury due to atherosclerotic plaque rupture and myocardial infarction. Therapeutic angiogenesis promoting the growth of new vessels from existing vessel wall cells, in conjunction with the recruitment of circulating endothelial progenitor cells (EPCs),is therefore viewed as a highly promising strategy to revascularise ischaemic tissues and thereby improve functional recovery of injured organs. A major goal of the EVGN is to identify genes involved in differentiation, homing and expansion of EPCs. 2.The EVGN acts as an interface between basic scientists and clinician scientists to promote and accelerate the transition of knowledge in vascular biology to improve diagnosis and treatment of atherothrombotic diseases. 3.The EVGN provides enriched and continued education in vascular biology. The EVGN proposes to train tomorrows leading investigators by creating a European training programme in vascular biology for PhD students based in part on a summer school. 4.The EVGN jointly manages,disseminates and promotes exploitation of the knowledge generated and accumulated within the network.
Expression of the Tissue Factor, the main initiator of thrombus formation in myocardial infarction (in red), in a human atherosclerotic plaque that contains debris from apoptotic cells (in brown)
The chosen study areas 1) endothelial dysfunction, 2) atherosclerotic plaque instability and 3) therapeutic angiogenesis represent three phases of the cardiovascular disease continuum. Endothelial dysfunction underlies atherosclerosis progression and is a fertile area for early diagnosis and prevention.Atherosclerotic plaque instability precipitates most life-threatening manifestations of atherosclerosis and as such is a key unexplored area for novel therapies, not based on risk factor modification but on targeting the pathology.Therapeutic angiogenesis is a leading edge new technology that promises to ameliorate end organ damage following acute cardiovascular events. In particular it may tackle the alarmingly escalating incidence of heart failure. Each of the three priority areas is ripe for the genomic approach, since each depends on understanding complex regulatory pathways in molecular detail. Each has potential for the development of new diagnostic and therapeutic strategies that will provide permanent benefits for patients.
Expected results
1.To define the molecular mechanisms underlying endothelial and smooth cell dysfunction and discover new preventive strategies in atherosclerosis. 2.To develop and standardise new animal models of plaque rupture, to improve non-invasive in vivo detection of unstable plaques, and to identify molecular targets whose selective activation/inhibition will tend to limit plaque progression or promote atherosclerotic plaque stability. 3.To identify novel genes, gene products, or signalling pathways that are involved in, and could be targets for, selective modulation of angiogenesis/vasculogenesis 4.To define the most suitable preventive and/or therapeutic strategies for use in clinical care of ischaemic vascular diseases.
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Coordinator
Dr Tedgui,Alain Inserm U541 Hpital Lariboisire 41 blvd de la Chapelle 75475 Paris - Cedex 10, France Tel: +33 1 44 63 18 66 Fax: +33 1 42 81 31 28 Email:Alain.Tedgui@larib.inserm.fr Project web-site: http://www.evgn.org/ Key words: cardiovascular disease, vascular biology, atherosclerosis, endothelium, angiogenesis, inflammation
Centre for Biopharmaceutical Sciences, University of Leiden,The Netherlands Department of Biochemistry,Academic Medical Center, University of Amsterdam,The Netherlands Universita Vita-Salute San Raffaele, Italy Institut fuer Pathophysiologie, Medizinische, Universitaet Innsbruck, Austria A.I.Virtanen Institute, University of Kuopio, Finland Institute for Cancer Research and Treatment, University of Torino, Italy Experimental Medicine and Gene Therapy Section, National Institute of Biostructures and Biosystems, Italy St George's Hospital Medical School, University of London, United Kingdom Department of Molecular Biology, Institute of Microbiology,The Hebrew University of Jerusalem, Israel Department of Reproductive and Vascular Biology, University of Birmingham, United Kingdom University College London, United Kingdom Division de Cardiologie, Fondation pour Recherches Mdicales, University Hospital of Geneva, Switzerland Centre Europen de Recherche en Biologie et en Mdecine, IGBMC, Illkirch, France Ark Therapeutics Group Limited, London, United Kingdom Technoclone GmbH,Vienna,Austria Inserm-Transfert SA, Pons, France
Partners
Bristol Heart Institute,The University of Bristol, United Kingdom Klinikum der J.W.Goethe-Universitt, Germany Chancellor, Masters and Scholars of the University of Cambridge, Addenbrookes Centre for Clinical Investigation, United Kingdom Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM),The Netherlands Center for Molecular Medicine, Karolinska Institutet, Sweden Fondazione IFOM Istituto FIRC di Oncologia moleculare, Italy University Hospital, Zrich, Switzerland Department of Vascular Biology and Thrombosis research, Medical University of Vienna, Austria Medizinische Klinik und Poliklinik, Johannes GutenbergUniversitt Mainz, Germany Klinik und Poliklinik Innere Medizin III, Universitt des Saarlandes, Germany Institute for Cardiovascular Research (ICaR-VU), VU Medical Centre,The Netherlands
Acronym: EVGN Project number: LSHM-CT-2003-503254 EC contribution: 9 000 000 Instrument: Network of Excellence Duration: 60 months Starting date: 01/01/2004
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MOLSTROKE
Molecular basis of vascular events leading to thrombotic stroke

Summary
Stroke kills about 5 million people annually and is also the leading cause of disability and dementia in adults. Early recognition of individuals at risk for stroke would significantly alleviate the heavy social and economical burdens due to stroke. Advances in identification of vulnerable individuals require development of entirely new strategies. Stroke is triggered by thrombosis occurring after rupture of atherosclerotic plaques, and MOLSTROKE focuses on identifying pathogenetic molecular mechanisms and vascular protagonists defining vulnerable plaques and contributing to plaque rupture. MOLSTROKE assembles seven partners with multidisciplinary backgrounds and exploits innovative technological approaches together with testing of novel pathogenetic hypotheses. The priority research areas of MOLSTROKE consist of 1) concomitant wide genomic and histoproteomic screening of lesional vascular tissue to identify novel pathogenetic markers, 2) early inflammatory events, which are the key to atherosclerosis progression and hence primary prevention, and 3) atherosclerotic plaque instability, which leads to the acute clinical thrombotic events. The proposed investigations will implement novel technologies of differential display of unknown genes and vascular tissue arrays.Thus, weighted identification of stroke denominators can be accomplished and thereby lead to improved diagnostic and treatment modalities. The research armoury spans genomics, tissue arrays, molecular biology, cell biology, immunology, biochemistry, gene transfer, animal models and integrative bioinformatic software tools. MOLSTROKE will maximise the scientific, educational and commercial potential of the proposal by electronic data-sharing, communication networks, shared research tools, and training programmes. to identify new markers to more appropriately predict the possible development of stroke and to identify those subjects with potential benefit from preventive therapy. Ischemic strokes account for 83% of all strokes and thrombotic strokes represent 52% of all ischemic strokes. Thrombotic stroke is a consequence of atherosclerotic disease and is caused by destabilisation of atheromatous plaque with ensuing thrombosis and vessel occlusion locally or distally due to embolism.A large body of data supports that inflammation plays a major role in the pathophysiology of atherosclerosis and stroke.Understanding the mechanisms responsible for the initiation, establishment, maturation and persistence of atherosclerotic lesions is far from being fully accomplished. The current research focus is the definition of new criteria to recognise vulnerable plaques and vulnerable patients. These criteria should be based on better definition of the pathogenetic mechanisms of plaque rupture. They should utilise inexpensive and relatively non-invasive screening methods that are capable of adding predictive value to measurements of established risk factors. Moreover, they should be readily applicable to an asymptomatic population.
Aim
The main scientific and technological goals of MOLSTROKE are to identify mechanisms and molecular protagonists that participate in the vascular pathological events leading to thrombotic stroke. MOLSTROKE addresses objectives using two concomitant strategies. The first strategy is non-hypothesis driven and will use wide-screening technologies together with novel bioinformatics tools to identify genes and proteins preferentially expressed in atheromatous plaques as well as molecular, biochemical, and cellular patterns potentially involved in plaque rupture. The second strategy is based on hypothesis-driven studies,taking into consideration current knowledge of the pathogenesis of vascular lesions at the level of molecular protagonists and mediators of inflammation and vascular cell responses to inflammation.
Expected results
identification of genes of potential pathogenetic importance generation and use of novel bioinformatics tools localise and quantify differentially expressed proteins in symptomatic atherosclerosis identify molecular targets of novel therapeutic approaches to prevent symptomatic atherosclerosis and stroke strategy for immunotherapy of atherosclerosis and stroke prevention
Problem
Stroke is a major killer since about 5 million people die each year of this disease. Stroke is also the major cause of disability in adults, and the second most important cause of dementia in western countries. Among those who survive a stroke,the risk of a second stroke is very high. Currently known risk factors for stroke (age, cardiovascular diseases, atrial fibrillation, arterial hypertension, diabetes mellitus, carotid stenosis) are of low sensitivity and specificity. It is important
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Coordinator
Prof. De Libero, Gennaro Experimental Immunology Department of Research University Hospital Basel 4030 Basel, Switzerland Phone: +41 61 2652365 Fax: +41 61 2652350 Email: gennaro.delibero@unibas.ch Prof. Resink,Therese Signal Transduction Department of Research University Hospital Basel 4030 Basel, Switzerland Email:Therese-J.Resink@unibas.ch Project web-site: to be constructed Key words: stroke, atherosclerosis, inflammation, angiogenesis, lipids, plaque instability
Partners
Dr Biedermann, Barbara Department of Internal Medicine University Hospital Bruderholz Binningen, Switzerland Prof. Hansson, Goran. K. Department of Medicine Karolinska Hospital and Center for Molecular Medicine Karolinska Institute Stockholm, Sweden Dr Bochkov,Valery Department of Vascular Biology and Thrombosis Research University of Vienna Vienna, Austria Prof. Ricciardi Castagnoli, Paola Universit Milano Bicocca Milan, Italy Prof.Wick, Georg Institute for Biomedical Ageing Research Austrian Academy of Sciences Innsbruck, Austria
Work flow in the MOLSTROKE project
strategy for lipid-based immunomodulation of atherosclerosis development of new therapeutic strategies (anti-inflammatory and/or anti-angiogenic) for prevention of thrombotic stroke translational impact to other diseases in which inflammation and excessive angiogenesis occur (e.g. cancer, diabetic retinopathy, arthritis, psoriasis)
Prevention and therapy of stroke.
Acronym: MOLSTROKE Project number: LSHM-CT-2004-005206 EC contribution: 2 300 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/01/2005
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EuroClot
Genetic regulation of the end-stage clotting process that leads to thrombotic stroke
Aim
We aim specifically to identify the major genes involved in variations of the end-stage clotting process and investigate the role of these novel genes (and existing candidate genes) in the pathogenesis of stroke across Europe. EuroClot will study stroke intermediate phenotypes in over 3000 twins from the GenomEUtwin project involving eight countries and 700 subjects from extended families. Genes will be validated in 1000 stroke cases including those from the large European prospective MORGAM study. CrossEuropean differences in allelic frequencies will be examined along with their relative impacts.Phenotyping will be standardised and harmonised and a European database established. Close links with European SMEs will ensure that all findings from EuroClot are maximally exploited to develop future novel diagnostics and therapeutic targets.
Expected results
Identification of susceptibility loci and genes for the end stages and final common pathways of clotting. Assessment of the importance of these genetic factors in the general European population. Discovery of how identified genetic variants vary in influence and frequency of stroke in Northern and Southern Europe. Identification of genes controlling fibrin formation or activation that will become important diagnostic tests used in conjunction with other markers or genes. Better understanding of the mechanisms involved providing potential new drug targets for the prevention or treatment of early stroke. Collaboration with SMEs to exploit findings for clinical benefit. Generation of genotypic and phenotypic data for concordant and discordant twin pairs for future studies evaluating environmental effects on stroke pathogenesis and expression. Stimulation of interest in thrombotic stroke research. Development of the clinical, genetic, and experimental EuroClot database. Position European researchers as leaders in clotting and stroke research.
Summary
Thrombotic stroke is a disabling condition affecting an estimated 650,000 Europeans annually, with considerable mortality and costing over 30 billion/yr. This project aims to unravel the genetic basis of thrombotic stroke leading to new diagnostics and drug targets.
Problem
Genetic factors account for a substantial component of the incidence and mortality of stroke.There is little effective therapy. EuroClot aims to identify and validate potentially therapeutically useful genes associated with thrombotic stroke using a novel approach. Stroke is a complex end-point disease involving the interaction of many pathologic processes, such as vessel wall atheroma, hypertension, platelet function & coagulation. EuroClot focuses on uncovering the genes that control the end-stage of the coagulation process that leads directly to the production of the thrombus (clot) that causes vascular obstruction and tissue death. Clinical studies indicate that alterations in fibrin structure and/or function create a prothrombotic phenotype, which increases vascular risk.Twin studies have shown a substantial genetic component to levels of activation peptides and the final common pathway of thrombus (fibrin structure/function).
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Coordinator
Prof. Spector,Tim Twin Research Unit St Thomas Hospital Lambeth Palace Road London SE1 7EH, United Kingdom Phone: + 44 20 7188 6765 Fax: + 44 20 7188 6718 E-mail: tim.spector@kcl.ac.uk Project web-site: in development Key words: cardiovascular system, stroke, genetic, clotting factors
Partners
Prof. Grant, Peter Academic Unit of Molecular Vascular Medicine Leeds Institute of Genetics, Health and Therapeutics Leeds General Infirmary Leeds, United Kingdom Prof. Rosendaal, Frits Department of Clinical Epidemiology Leiden University Medical Centre Leiden,The Netherlands Prof. Palotie,Aarno Finnish Genome Centre University of Helsinki, Helsinki, Finland Prof. Evans,Alun Department of Epidemiology and Public Health Mulhouse Building Belfast, United Kingdom Dr Stazi,Antionia Centro Nazionale di Epidemiologia Sorveglianza e Promozione della Salute (CNESPS) Rome, Italy Prof. Pedersen, Nancy Department of Medical Epidemiology and Biostatistics Stockholm, Sweden
Acronym: EuroClot Project number: LSHM-CT-2004-005268 EC contribution: 1 500 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/01/2005
Potential new drug targets for the prevention of or treatment of early stroke by reducing the tendency to clot. Development of novel therapeutic targets for the prevention of thrombotic stroke using translational approaches in collaboration with appropriate SMEs in Europe. Development of potential novel diagnostic tests for stroke risk using combinations of clotting factors and genetic tests in collaboration with SMEs in Europe.
Prof. Soria, Jose Manuel Thrombosis and Haemostatis Unit Hospital de la Santa Creu i Sant Pau Barcelona, Spain
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Myocardial Repair
Clinical experience with bone marrow cells and myoblasts transplantation for myocardial repair
Summary
Heart failure caused by ischaemic heart disease is one of the most common causes of morbidity and mortality across Europe. It is especially high among elderly people, but post-infarction myocardial injury is also a major cause of disability in younger survivors from myocardial infarction.The project is dedicated to stimulate state-ofthe-art research on the clinical applications of autologous stem cells, including bone marrow-derived stem cells as well as myoblasts, to the regeneration of heart muscle in irreversibly damaged post-infarction regions.The consortium includes most experienced European clinical researchers in the field, which already had accomplished the phase I clinical trials in participating centres. The researchers from participating centres have agreed to coordinate their future clinical trials on stem cell transplantation for myocardial regeneration in patients with post-infarction heart failure, as a result of the proposed project. This will include analysis of pooled clinical data obtained in participating centres, reciprocal exchange of information on cell culture and cell preparation for transplantation. This will also include standardisation of clinical protocols aiming at evaluation of the clinical efficacy of myocardial replacement therapy as well as hands-on training of different techniques of cell delivery, including percutaneous cell transplantations, in particular transcoronary arteries bone marrow stem cell delivery protocols as well as trans-ventricular and trans-cardiac-veins myoblast injection techniques.As a result of further integration of the consortium, it is expected to stimulate formation of a common future phase III studies at international level, especially with an option of submitting future Integrated Project application within the 6th Framework Programme. The current project of a Specific Support Action project is focused on coordination of individual studies and integration for future panEuropean research. Thus, the continuation of the current clinical experiments within phase I and II studies will be performed with resources from each participating centre. The intention of this SSA project is to enable the consortium to make appropriate exchanges of information, reciprocal training visits as well as co-operative analyses of pooled data. Summary of existing pooled data will be submitted for publication by participating team leaders. In addition, two international conferences on stem cell therapies and three workshops for practitioners will be organised.
Problem
Heart failure due to myocardial infarction is a result of myocardial tissue loss. Preclinical research and initial clinical experience suggests a possibility of myocardial regeneration by cell transplantation.
Aim
The purpose of the project is to enhance the exchange of information on clinical experience with cell transplantation between leading research groups and to summarise the European experience with myoblast and bone marrow-derived cells transplantation in patients with post-infarction heart failure.
Expected results
It is assumed, that as a result of the proposed project, the exchange of information and co-operative reciprocal visits in participating centres would further advance clinical research aiming at the myoblast transplantation in comparison to other totipotent cells as bone marrow cells for myocardial regeneration.
Establishing clinical protocols for the use of cell transplantation for the treatment of post-infarction heart failure.
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Coordinator
Siminiak,Tomasz University School of Medical Sciences, Poznan Department of Cardiology Ul. Juraszow 7/19 60-479 Poznan, Poland Phone: +48 61 8212422 Fax: +48 61 8212 319 tomasz.siminiak@usoms.poznan.pl Project web-site: under construction Key words: cardiology, medicine, muscle system, stem cells, organ regeneration, cell therapy
Partners
Hpital Europen Georges Pompidou, Paris, France Instut de Ciencias del Corazon,Valladolid, Spain University of Rostock, Germany 3rd Medical School, Charles University Prague, Czech Republic University Hospital, Clermont-Ferrand, France Vilnius University, Lithuania Polish Academy of Science, Poznan, Poland University of Rotterdam,Thoraxcenter,The Netherlands
Acronym: Myocardial Repair Project number: LSSM-CT-2004-511992 EC contribution: 400 000 Instrument: Specific Support Action Duration: 30 months Starting date: 01/01/2005
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Diabetes
Diabesity EXGENESIS EUGENE 2 TONECA IMMIDIAB 32 34 36 39 41
DIABETES
Diabesity
Novel molecular targets for obesity and type 2 diabetes

Summary
The Diabesity project brings together basic and clinical scientists with the joint aim of identifying new genes implicated in obesity and diabetes (diabesity) and to develop strategies for validating these genes as targets for future pharmacological manipulation.We will study how these genes interact with hypothalamic pathways that regulate appetite and metabolism using multiple approaches to establish the functional role of genes in regulating metabolism, body weight and composition. Using this approach we aim to identify several novel, validated drug targets for the treatment and prevention of diabesity.
Expected results
Using a combination of invertebrate and mammalian genetics, Diabesity expects to firstly identify several genes involved in the pathogenesis of diabesity.These potential drug targets will then be characterised by molecular and physiological studies resulting in the localisation of the site of expression of the targets and an under standing of their functional roles in diabesity. Once characterised, potential targets will (by molecular genetics and phenotypical analyses) be identified as playing major roles in diabesity, thereby providing validated novel drug targets and pharmaceutical therapies that appropriately address diabetes and obesity.
New knowledge generated by Diabesity, primarily novel drug targets and potential pharmaceutical therapies, will be translated into applications that directly enhance human health by bringing basic knowledge through to clinical application. To this end, both fundamental and applied research will be supported,with an emphasis on integrated, multidisciplinary, and coordinated efforts that address the present fragmentation of European research and increase the competitiveness of the European biotechnology industry.By identifying potential new drug targets for the treatment and prevention of diabesity we will provide pharmacological and biotechnological SMEs with the possibility to develop novel pharmaceutical therapies.
Problem
The rapid increase in the prevalence of obesity, type-2 diabetes, and associated complications is a major global health problem. In Europe alone, approximately 33 million adults will be suffering from diabetes by 2010. Obesity, which is a major recognised risk factor for type-2 diabetes,is itself rapidly increasing in prevalence resulting in a diabesity epidemic.The current cost of type-2 diabetes in the European Union is 15 billion per year, and medical complications arising from diabetes account for up to 8% of total health costs in Europe. For most people, neither dieting nor current pharmacological interventions are effective in achieving long-term weight reduction. Dieting is largely ineffective because once a chronically overweight state has been attained,the brain interprets dieting as a threat to survival, and the hypothalamic control systems of the brain reduce our metabolism and attempt to maintain body weight, i.e. our brains defend our existing energy stores.Thus to prevent and treat diabesity, we must develop approaches to modulate the ways in which the brain controls metabolism, body weight and composition.
Coordinator
Prof. Dickson, Suzanne L. Prof. Dickson, Suzanne L. Department of Physiology, Medicinaregatan 9A Gteborg University Box 434 405 30 Gteborg, Sweden. Phone: +46 31 773 3568 E-mail: suzanne@medic.gu.se Project web-site: www.eurodiabesity.org/ Key words: diabetes, obesity, metabolism, drug targets, diabesity
Aim
Diabesity aims to combine neurophysiological, neuroanatomical, and systems physiological approaches to establish the functional role of genes in regulating body composition, in order to understand how manipulation of gene activity impacts upon whole body physiology, endocrinology and phenotype. We will identify novel genes and processes linked to the pathogenesis of diabesity and thereby find potential molecular drug targets. Characterisation of those drug targets, in particular by using molecular physiological studies and integrative human biology, will be followed by target validation resulting in the identification of several novel, validated drug targets for the treatment and prevention of diabesity.
Partners
Prof.Astrup,Arne The Royal Veterinary & Agricultural University Department of Human Nutrition, Rolighedsvej 30 Frederiksberg C, Denmark
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DIABETES
Dr Barroso, Ins The Wellcome Trust Sanger Institute The Wellcome Trust Genome Campus Hinxton, Cambridge, United Kingdom Prof. Bloom, Steve Department of Metabolic Medicine Imperial College School of Medicine Hammersmith Hospital, London, United Kingdom Dr Steuernagel,Arnd DeveloGen AG Gttingen, Germany, Prof. Brning, Jens C Klinik II und Poliklinik fr Innere Medizin der Univesitt zu Kln Cologne, Germany Dr Cox, Roger D MRC Mammalian Genetics Unit, Medical Research Council Harwell, Oxfordshire, United Kingdom Prof. Dieguez, Carlos Universidad de Santiago de Compostela Spain Prof. Enerbck, Sven Medical Genetics, Department of Medical Biochemistry, Gteborg University, Sweden Prof. Ghigo, Ezio Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin Torino, Italy, Dr Grosse, Johannes Ingenium Pharmaceuticals AG, Munich, Germany, Dr Hager, Jorg IntegraGen SA, 4, Evry, France Prof. Hebebrand, Johannes Child and Adolescent Psychiatry of the Rheinischen Kliniken of the University of Duisburg-Essen, Germany Prof. Jansson, John-Olov Division of Endocrinology Sahlgrenska Hospital, Gteborg University Sweden Prof. Leng, Gareth School of Biomedical and Clinical Laboratory Sciences University of Edinburgh College of Medicine Edinburgh, United Kingdom Prof. Liposits, Zsolt Institute of Experimental Medicine Laboratory of Endocrine Neurobiology,
Budapest, Hungary Prof. Meister, Bjrn Department of Neuroscience, Karolinska Institute Stockholm, Sweden Dr Mercer, Julian Molecular Neuroendocrinology GroupAppetite and Energy Balance Division, Rowett Research Institute, Bucksburn Aberdeen, United Kingdom Prof. Nolan, John Metabolic Research Unit, Dept of Clinical Medicine (Endocrinology) Trinity College Dublin, St Jamess Hospital Dublin, Ireland Prof. ORahilly, Steve University of Cambridge Department of Clinical Biochemistry Addenbrookes Hospital Cambridge, United Kingdom Dr Pagotto, Uberto Endocrine Unit Dept. of Internal Medicine and Gastroenterology S.Orsola-Malpighi General Hospital Bologna, Italy Prof. Ricquier, Daniel Facult de Mdecine Necker-Enfants Malades Paris, France Prof. Rohner-Jeanrenaud, Franoise Laboratory of Metabolic Research Division of Endocrinology, Diabetology and Nutrition Department of Medicine and of Morphology Geneva, Switzerland Prof. Seckl, Jonathan Molecular Medicine Centre Western General Hospital, Edinburgh, United Kingdom Prof. Staels, Bart Institut Pasteur de Lille Lille, France Prof.Treier, Mathias European Molecular Biology Laboratory Developmental Biology Programme Heidelberg, Germany Prof.Tschp, Matthias Dept. of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbrcke, Germany
Acronym: Diabesity Project number: LSHM-CT-2003-503041 EC contribution: 11 700 000 Instrument: Integrated Project Duration: 60 months Starting date: 01/01/2004
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DIABETES
EXGENESIS
Health benefits of exercise: identification of genes and signalling pathways involved in effects of exercise on insulin resistance, obesity and the metabolic syndrome
Summary
Europe faces an epidemic of obesity, Type 2 diabetes and the metabolic syndrome. Obesity and insulin resistance, which can be regarded as precursors of Type 2 diabetes,arise due to an imbalance between energy intake and energy expenditure. Regular exercise, combined with an improved diet, provides protection against, and an effective treatment for, these conditions.This Integrated Project aims to provide a better understanding of the molecular mechanisms involved in the protective effects of exercise and a healthy diet,especially in terms of the signalling pathways,and the changes in gene expression,involved.These improved insights should allow the more rational design both of new pharmaceutical interventions, and of policies designed to improve the health of the population through improvements in lifestyle. capitalise on these new advances and begin the process of converting them into new measures for prevention or treatment of disease. Our proposal would establish a consortium that will execute an Integrated Project on this topic in a truly multidisciplinary manner. Our combined academic expertise ranges across molecular and cell biology,use of animal models including transgenic mice,human muscle physiology, diabetic medicine, and human epidemiology, genetics and interventional studies. Some of the methodologies we use include:
Problem
The European Union, like the rest of the developed and developing world, is facing a major epidemic of three inter-related chronic conditions, i.e.Type 2 diabetes, obesity and the metabolic syndrome. Unless steps are taken to alleviate this crisis, the cost of treating the long-term consequences of these conditions could overwhelm our healthcare systems. Although genetic factors increase the risk of developing these conditions, their rapid current global rise can only be due to environmental factors. Obesity and insulin resistance, both of which can be regarded as precursors of Type 2 diabetes, arise due to an imbalance between energy intake and energy expenditure.This in turn may be due to two features of the modern urban lifestyle: (i) frequent consumption of processed foods with high energy and low fibre content; (ii) reduction in the amount of exercise taken due to changes in social and transport patterns. It is now well established that regular exercise, combined with an improved diet, provides protection against the development of these conditions, as well as a first line of treatment.
Studies of changes in protein localisation in live muscle fibres, using fluorescent proteins
1) Molecular biological manipulation of signalling pathways in cultured cells and in animal models, such as in vivo tranfection of DNA into mouse muscle (e.g. Fig. 1) 2) Metabolic studies of muscle during exercise and after exercise training in male and female human volunteers, both in healthy subjects or those with Type 2 diabetes (e.g. Fig. 2) 3) Collection of clinical data, and DNA samples for genetic analysis, from families containing subjects with and without Type 2 diabetes, across large European regional populations (e.g. Fig. 3). The consortium also includes two major European companies involved in pharmaceutical and food production, and two small-tomedium enterprises involved in developing new technologies relevant to our aims.
Aim
Recent major scientific advances (in which partners in this project have played a prominent part) have begun to unravel the signalling pathways,and changes in gene expression,in muscle and other tissues through which the beneficial effects of regular exercise arise.The aim of this proposal is to establish a major European consortium that will
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DIABETES
Expected results
1) Identify and delineate the intracellular signalling pathways that mediate the effects of exercise in skeletal muscle of males and females. 2) Identify the mechanisms leading to release by muscle during exercise of extracellular factors,such as cytokines,that affect insulin resistance and transmit effects of exercise to other sites such as adipose tissue,the liver and endothelial cells,and study their action at those sites. 3) Identify the signalling mechanisms stimulating release of fatty acids and cytokines (adipokines) from adipose tissue during exercise and fasting. 4) Establish whether mutations affecting any of the signalling pathways involved in effects of exercise could predispose to Type 2 diabetes, obesity or the metabolic syndrome in humans. 5) Delineate patterns of expression of genes and proteins in humans at risk of developing Type 2 diabetes and in cohorts of monozygotic and dizygotic twins of known health status. 6) Validate potential new drug targets identified during the research, using small molecule inhibitors or activators, expression of constitutively active or dominant negative mutants, siRNA technology, or gene targeting in mice. 7) Develop technologies that enable screening of drugs using immortalised human muscle cells, and more effective long-term monitoring of human physical activity and cardiac function.
These measures could take the form of new pharmaceutical interventions based on the identification of signalling pathways or proteins responsible for the health benefits of exercise,or of new policies at local, national or EU level that produce beneficial changes in the lifestyles of the population, especially in terms of diet and exercise.
Coordinator
Prof. Hardie, D Grahame Division of Molecular Physiology Faculty of Life Sciences University of Dundee Wellcome Trust Biocentre Dow Street Dundee DD1 5EH, Scotland, United Kingdom Phone: +44 1382 344253 Fax: +44 1382 345783 Email: d.g.hardie@dundee.ac.uk Project web-site: http://www.dundee.ac.uk/lifesciences/exgenesis/ Key words: exercise, genes, signalling pathways, diabetes, obesity, metabolic syndrome
Partners
5 Denmark 1 Belgium 2 France 1 Finland 3 Sweden 5 United Kingdom 2 Spain 1 Switzerland 1 Czech Republic 1 The Nederlands 1 Italy 1 Germany 1 Poland
Metabolic studies during exercise in female and male volunteers
New insights gained in this project will provide an evidence base to allow the more rational design of measures aimed at reducing the large burden of Type 2 diabetes,obesity and the metabolic syndrome in the population.
Acronym: EXGENESIS Project number: LSHM-CT-2004-005272 EC contribution: 12 700 000 Instrument: Integrated Project Duration: 60 months Starting date: 01/01/2005
35
DIABETES
EUGENE2
European network on functional genomics of Type 2 Diabetes

Summary
EUGENE2 is a Network of Excellence focused on functional genomics, genomics, proteomics and bioinformatics to unravel the complex pathogenesis of Type 2 diabetes and the specific role of the skeletal muscle, fat and the liver. This involves the dedication and the development of common research infrastructures in human and rodent genomics and bioinformatics combined with cohesive research efforts in proteomics, transcriptional regulation, insulin signalling and action in the target tissues. A concerted effort in applying functional genomic approaches in target cells,rodents,and humans will generate information necessary to make advances in health care,pharmaceutical development and public health policies. bringing together specific expertise in the required areas of celland molecular biology, rodent models, biology of target organs for insulin action (skeletal muscles, adipose tissue and liver) as well as combined access to unique patient populations allowing functional genomic and genetic studies. The establishment of common research protocols, technical platforms and databases will promote durable and sustainable integration.The increased critical mass and the joint efforts of scientists with complementary expertise will allow EUGENE2 to advance the current state of the art and provide new insights into the pathogenesis of Type 2 diabetes and to improve existing therapy.
Aim
Many steps are taken to strengthen European diabetes research and to reduce fragmentation.These include indirect integrating activities based on jointly executed research (JER), and direct integrating activities: coordinated programming of research in order to strengthen the complementarity of the participants sharing of common research tools and platforms joint use of infrastructures exchange of staff and training programmes integrated management of knowledge and intellectual property and implementation of a Joint Strategy for Immaterial Property rights.
Problem
Type 2 diabetes is a complex polygenic disease where genetic susceptibility interacts with environmental factors.An early event in the development of Type 2 diabetes is insulin resistance, i.e., an impaired effect of insulin in the target tissues (muscle, adipose tissue and liver). Although the metabolism and function of all these tissues are altered in the diabetic state, it is currently unknown if, and to what extent, these changes are secondary to the diabetic state or if they are initiating events in the development of the disease. To comprehensively study the pathogenesis of as complex a disease as Type 2 diabetes requires a broad array of experimental technologies, access to different experimental models (cells and animals), expertise in muscle, adipose tissue and liver biology as well as wellcharacterised human populations with the disease and genetically predisposed individuals who have not yet developed Type 2 diabetes. Consequently, no single research group in Europe has the capacity to comprehensively study such a complicated disease. The existing fragmentation of diabetes research in Europe is an important obstacle to success. EUGENE2 integrates top scientists in diabetes research in Europe, thereby
The Joint Programme of Activities of EUGENE 2
36
DIABETES
Graphical presentation of the research components of EUGENE 2 and their relationships
reinforcement of electronic information and communication networks. The jointly executed research is focused on generating new knowledge to fill existing gaps as well as to develop platforms for common use. A JER programme is, by definition, an instrument for integration. Although intensive research has been focused on the genetics of Type 2 diabetes during many years,major genes contributing to this disease remain largely unknown. Each partner in EUGENE2 will bring unique expertise to the project together with particular models or experimental techniques such as: unique patient populations and phenotyping procedures combined with functional genomics and/or genetics unique animal models and their characterisation signal transduction and engineered cell models peptide synthesis and drug discovery.
Expected results
1. Promoting integration through the establishment of common research platforms for bioinformatics, novel reagents and cell lines, RNA and DNA samples, proteomics and engineering and phenotyping animal models. 2. Jointly executed research to identify novel genes related to Type 2 diabetes. Success in this endeavour will have major health implications for both the diagnosis and treatment of Type 2 diabetes. 3. Characterising the function of genes related to insulin resistance and Type 2 diabetes as well as their genomic associations and/or linkage. 4. Establishing joint training programmes and scientist exchange programmes to strengthen European research expertise in this field. 5. Strengthening the European pharmaceutical and biotechnology industries through research collaboration and policy for protection of knowledge.
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DIABETES
Coordinator
Prof. Smith, Ulf Lundberg Lfaboratory for Diabetes Research, Dept. of Internal Medicine, Sahlgrenska Academy at Gteborg University 413 45 Gteborg, Sweden Phone: +46 31 3421104 Fax: +46 31 829138 Email: ulf.smith@medic.gu.se Project web-site: www.eugene2.com (to be established). Key words: diabetes, insulin resistance, cardiovascular disease, adipose tissue, liver, skeletal muscles
Karolinska Institutet Section of Integrative Physiology Dept. of Surgical Science Stockholm, Sweden Prof. Joost, Hans-Georg Dept. of Pharmacology German Institute of Human Nutrition Potsdam-Rehbruecke Potsdam-Rehbrcke, Germany Prof. Beguinot, Francesco Dipartimento di Biologia e Patologia Cellulare e Molecolare (DBPCM) II Facolt di Medicina Naples, Italy Prof.Van Obberghen, Emmanuel Inserm Unit 145 Facult de Mdecine Nice, France Prof.Auwerx, Johan Institut Clinique de la Souris Illkirch, France Prof. Bosch, Fatima Center of Animal Biotechnology and Gene Therapy (CBATEG) Universitat Autnoma de Barcelona (UAB) Bellaterra, Spain Director Levens, Nigel Biovitrum AB, Stockholm, Sweden
Partners
Prof. Laakso, Markku Department of Medicine University of Kuopio Kuopio, Finland Prof. Hring, Hans-Ulrich Medizinische Universittsklinik Tbingen, Germany Prof. Sesti, Giorgio Department of Experimental and Clinical Medicine University Magna Graecia of Catanzaro Catanzaro, Italy Prof. ORahilly, Stephen Clinical Biochemistry Addenbrooks Hospital Cambridge, United Kingdom Prof. Pedersen, Oluf Steno Diabetes Center Gentofte, Denmark Prof. Zierath, Juleen R
Acronym: EUGENE2 Project number: LSHM-CT-2004-512013 EC contribution: 8 000 000 Instrument: Network of Excellence Duration: 48 months Starting date: 01/11/2004
38
TONECA
DIABETES
Coordination action on the aetiology, pathology and prediction of Type 1 diabetes in Europe
Summary
Type 1 diabetes mellitus (T1DM) imposes a heavy burden of morbidity and premature death on more than 2 million inhabitants in Europe.To identify new targets for prevention, diagnosis and treatment of T1DM, greater understanding of its aetiology and pathology is crucial. This requires the elucidation of the cellular and molecular mechanisms responsible for T1DM through bringing together leading European centres of expertise in the field of clinical and experimental T1DM research.The capabilities of the European groups participating in this coordination action (CA) provide the required technical skills and innovative advances. European diabetes research expertise in T1DM as assembled in this CA proposal will enable the coordination of RTD projects which are already in receipt of funding for the research part. The research topics to be coordinated in this CA deal with (a) molecular mechanisms of beta cell death and signalling pathways of apoptosis in T1DM; (b) the impact of environmental factors upon the genetically based regulation and progression of T1DM; (c) the use of established and new animal models to unravel the molecular mechanisms of the aetiology and pathology of T1DM; (d) the role of the cellular immune system in the pathogenesis of T1DM.The financial support for this CA will allow the running of the coordination activities.This will make it possible to better understand the underlying causes of T1DM with the aim of identifying targets for prevention, diagnosis and treatment. This will be achieved in particular through Coordination of common clinical and experimental studies and experiments on T1DM. Organisation of conferences,workshops and expert group meetings. Organisation of the exchange of personnel. Exchange and dissemination of ethical principles and good practice in clinical and experimental diabetes research through setting up common information systems and expert groups. Running of a central network resource for collection,quality control, storage and dissemination of biological materials.
Expected results
The results of this CA will be: Increased knowledge and new expertise in T1DM research. Education of young and advanced scientists in T1DM research. Exploitation of the acquired knowledge for the development of new therapeutical concepts for the prevention, diagnosis and treatment of T1DM. The new knowledge achieved through this CA will be, in particular, a better understanding of: Molecular mechanisms of immune mediated beta cell death and signalling pathways of apoptosis in T1DM, oxidative stress and cytokines. Impact of environmental factors upon the genetically based regulation and progression of T1DM. Role of the cellular immune system in the pathogenesis of T1DM, the role of the T cells and the identification of triggering factors of the autoimmune reaction. Both in human studies and through the use of established and new T1DM animal models, unraveling the molecular mechanisms of the aetiology and pathology of T1DM.
Problem
Type 1 diabetes mellitus (T1DM) is a complex multigenic disease with a large socio-economic impact. It is the most frequent metabolic disease in children and affects around two million children and adults in Europe.In many areas of Europe the incidence of T1DM is increasing and affecting children at a progressively younger age.
Aim
The aim of this CA is to use advanced genomics to detect triggers of autoimmunity and regulators of progression as well as mechanisms of cell death in well-characterised patient cohorts and experimental model systems with the aim of identifying targets for prevention, diagnosis and treatment. To achieve this aim the CA will promote and support the networking and coordination of research and innovation activities in the field of T1DM in Europe.
Due to the increasing incidence of T1DM in Europe there is an urgent need for the development of new preventive and curative therapies of this disease. The activities of this Coordination Action will allow the identification of new targets for prevention, diagnosis and treatment of T1DM. This understanding will help to provide the rational basis for the development of new pharmaceutical and gene therapies against this serious disease.
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DIABETES
Coordinator
Lenzen, Sigurd Institute of Clinical Biochemistry Hannover Medical School 30625 Hannover, Germany Phone: + 49 511 532 6525 Fax: + 49 511 532 3584 E-mail: Lenzen.Sigurd@MH-Hannover.de Project web-site: http://www.mhhannover.de/institute/clinbiochemistry/toneca Key words: Type 1 diabetes, beta cell apoptosis, autoantibodies, immunology, animal models
College Dublin, Ireland INSERM Unit 457, Robert Debr Hospital, Paris, France Development & Reproductive Biology, Biomedicum Helsinki, Finland Steno Diabetes Centre, Gentofte, Denmark Department of Immunohaematology & Blood Tranfusion, Leiden University Medical Centre, the Netherlands Department of Endocrinology and Metabolism, University of Pisa, Italy Enterovirus Laboratory, National Public Health Institute, Helsinki, Finland LEGENDO, UZ Gasthuisberg O&N, Leuven, Belgium Department Medical Biochemistry, Ernst-Moritz-ArndtUniversity, Germany Endocrine Unit, Hospital Universitari de Bellvitge, Barcelona, Spain Dept of Medical Cell Biology, Uppsala University, Sweden Institute of Biomedical & Clinical Science, Peninsula Medical School, United Kingdom
Partners
Department of Pharmaceutical Sciences, Aston University, United Kingdom School of Biomedical Sciences, University of Ulster, United Kingdom CeeD, Centre europen dtude du Diabte, France Diabetes & Metabolism Unit, Medical School, Southmead Hospital, Bristol, United Kingdom School of Pharmacy & Biomolecular Sciences, United Kingdom Endocrinology & Diabetes Unit, University of Barcelona Medical School, Spain Immunology of Diabetes Unit, San Raffaele Scientific Institute, Milan, Italy Pharmacy and Biomolecular Sciences, University of Brighton, United Kingdom Dept. of Internal Medicine Endocrinology, University of Siena, Italy Laboratory of Pharmacodynamics, Universit Libre de Bruxelles, Belgium Laboratory of Experimental Medicine, Universite Libre de Bruxelles, Belgium GKT School of Biomedical Sciences, Kings College London, United Kingdom Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden Childrens Hospital, University of Tbingen, Germany Lilly Research Laboratories, Hamburg, Germany Department of Biochemistry Institution, University
Acronym: TONECA Project number: LSHM-CT-2004-503245 EC contribution: 1 000 000 Instrument: Coordination Action Duration: 48 months Starting date: 01/06/2004
40
IMMIDIAB
DIABETES
Genetic susceptibility for Type 2 diabetes and obesity among immigrants in Europe: Prevention and treatment
Summary
The epidemiology of Type 2 diabetes and its complications vary significantly between ethnic groups. Immigrants in western Europe, particularly from the South-Asian countries, appear to represent the epidemic challenge to understand the genetic predisposition and its interfaces with the adaptability to new environmental conditions for the development of Type 2 diabetes mellitus (T2DM). Communities undergoing transitory lifestyles offer an ideal opportunity to gain insight to the patterns of genetic predispositions and their complex interplay with lifestyle that may explain the increasing prevalence of obesity and T2DM in Europe and the rest of the world today. The relationships between the conditions like obesity, T2DM and insulin resistance and impaired insulin secretion are complex. They may have some common genetic traits and endocrinological features but the pathophysiology responsible for the development of hyperglycaemia in Type 2 diabetes is yet to be established. Obesity stands out as a risk factor for T2DM, but lean Type 2 diabetes was also observed in India and Bangladesh. Recent observations of extremely lean, lipoatrophic models have revealed a similar predisposition to developing diabetes as with those with increased adiposity. Further investigations are needed in the adipose tissue and its dysfunction in the pathogenesis of diabetes. Proteomics are necessary in these investigations. The thrifty phenotype hypothesis, introduced by Hales and Barker in 1992, proposed the concept that environmental factors acting in early life might influence later risk of Type 2 diabetes.This may obviously have played a role in the increased development of Type 2 diabetes among immigrants to Europe. Reduction of obesity is the core point in the treatment of diabetes in all ethnic groups. Reduced calorie intake and increased physical activity are the main treatment issues for both the conditions.Individualisation of treatment may be enhanced by further studies in genetic epidemiology. The understanding of the etiology and mechanism causing increased hyperglycaemia in this population will provide clues to more effective treatment and prevention of diabetes and obesity. Furthermore, the There is a need to organize cohesive efforts from various specialties like obesity and T2DM in genetics, bioinformatics, cell biology, clinics, epidemiology, and prevention. information may help in understanding the pathophysiology of T2DM in other population and thereby methods of treatment and prevention in general.Since the ethnic mix of the European population is changing rapidly,the identification of the mechanism involved in Type 2 diabetes is also important for the other ethnic groups.
Problem
To understand the genetic predisposition and its interfaces with the adaptability to new environmental conditions for the development of Type 2 diabetes mellitus. Complex interplay with the lifestyles that may explain the increasing prevalence of obesity and T2DM in Europe and the rest of the world today. To explain the pathophysiology responsible for the development of hyperglycaemia in T2DM. To provide clues to more effective treatment and prevention of diabetes and obesity.
Aim
Create a network of specialists of obesity and T2DM in genetics, bioinformatics and cell biology, clinics, epidemiology and prevention through three workshops,two training program and one international conference: 1. to train new researchers; 2. to conduct a small-scale genetic study of obesity and T2DM and of lifestyle in available immigrant populations in Oslo, London and Helsinki (funded outside the present project); 3. to contribute to develop bioinformatics; 4. to plan a bigger study of genetics and lifestyle across ethnicity.
41
DIABETES
Expected results
Reports and review articles from the workshops will be made.Two training courses for new researchers will be arranged.At the end of the period, an international conference will be held. Three workshops will address different aspects of the mentioned conditions. Reports and review articles will be made in order to provide new information and to identify needs and develop protocols accordingly for future research. The current project will contribute to better identifications of different subtypes, first, by summing up present knowledge, and second, by planning and making concerted research on genetics, epidemiology and clinical conditions together with obesity.
Coordinator
Prof. Claussen, Bjrgulf University of Oslo Pb. 1130-Blindern 0318 Oslo, Norway Phone +47 2 285 0614 Fax: +47 2 285 0610 Email: bjorgulf.claussen@medisin.uio.no Project web-site: www.med.uio.no/iasam/arbeidstrygd/immidiab Key words: Type 2 diabetes, obesity, genetics, lifestyle
The overall aim is to provide qualified suggestions to policymakers and to different interest groups for the development of prevention and treatment strategies for people at risk across different genotypes, clinical diagnoses, lifestyles and cultures. The ultimate objective for the network is to plan a bigger study of genetics and lifestyle across ethnicity in Europe. In order to implement the plan we must be able to bridge the fragmented research and form a cohesive approach.
Partners
University of Rome TorVergata, Italy kBioscience Ltd, Cambridge, United Kingdom The European Association for the Study of Diabetes, Dusseldorf, Germany Diabetic Association of Bangladesh Diabetic Association of Pakistan University of Malmo, Sweden London University, United Kingdom University of Helsinki, Finland WHO collaborating Centre on Diabetes in India University of Geneva, Switzerland
Acronym: IMMIDIAB Project number: LSHM-CT-2004-504839 EC contribution: 200 000 Instrument: Specific Support Action Duration: 18 months Starting date: 01/03/2004
42
Rare diseases
Eumitocombat Euroglycanet GENESKIN EuroWilson PWS EUGINDAT EURAPS AUTOROME Orphanplatform 44 47 49 52 56 58 60 62 64
RARE DISEASES
Eumitocombat
Rational treatment strategies combating mitochondrial oxidative phosphorylation disorders

Summary
Defects in the mitochondrial oxidative phosphorylation (OXPHOS) system,the principal circuit for cellular energy production,lead to often fatal, multi-system disorders affecting organs and tissues with a highenergy demand. The Eumitocombat consortium, consisting of 12 partners and encompassing 21 scientific groups from nine different countries, aims to integrate and extend knowledge on basic aspects of OXPHOS biology and the patho-biological cascades underlying OXPHOS disease manifestation in humans.All of the major European groups active in the forefront of OXPHOS research will participate in the project, including the Nobel Prize laureate, Sir John Walker. The Eumitocombat project will reinforce Europe as the international leader in the development of treatments capable of combating these disorders. To this end we will: integrate clinical and model-system expertise characterise important genes and proteins involved in the formation and regulation of the OXPHOS-system study the network of components involved in cellular energy metabolism by functional genomics develop more efficient genetic and protein (mutation) screening methods evaluate the cellular alterations/adaptations of these defects in specified cells, tissues, models and humans develop methods to target and test therapeutic agents to specific (sub)cellular locations. The contribution of mtDNA mutations to human disease was already recognised in the late 1980s,when maternally inherited point mutations, as well as clonally inherited mtDNA deletions arising spontaneously during development,were found to be associated with rare neurological syndromes.Since then,three further advances in our understanding have greatly expanded the field of mitochondrial OXPHOS disorders: The mtDNA genotype has been found to be a significant contributor to a range of relatively common,complex or heterogeneous disorders, including diabetes, sensorineural deafness and cardiomyopathy. Many nuclear genes that play roles in mtDNA maintenance or expression have also been found to be involved in disease, including some disorders whose mitochondrial basis was not previously recognised. More controversially, the demonstrable alterations to mtDNA during aging have given rise to the idea that somatic mutation of mtDNA as a result of oxidative damage may play a functionally significant role in the degenerative processes of aging itself. Despite a relative explosion of knowledge in the past decade, mitochondrial OXPHOS disease remains essentially intractable. Furthermore, it is also devastating in its impact on patients and their families. For all these reasons, new knowledge about mtDNA, about the OXPHOS system and its biogenesis, and about the cellular, developmental and physiological consequences of OXPHOS dysfunction, is urgently needed, in order to establish a feasible therapeutic strategy to treat these debilitating disorders.
Problem
Mitochondrial DNA (mtDNA), and the machinery that maintains and expresses it, constitute a partially autonomous genetic system within eukaryotic cells. Present in hundreds or even thousands of copies per cell, with the possibility of heteroplasmy (mixtures of mtDNA of different genotypes), maternal inheritance, and dependence upon hundreds of diverse nuclear genes for its function, mtDNA is also subject to unique rules. Moreover,the functions that it encodes -13 key subunits of the OXPHOS complexes,plus the translational RNAs needed to synthesise them - are essential for life, being at the core of energy metabolism.Therefore, it is not surprising that the genetic fitness of mtDNA is crucial for health.
Model of human complex I, with the various subunits
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RARE DISEASES
4. to apply the knowledge gathered from such approaches to the rational design and testing of therapeutic agents and manipulations to ameliorate the manifestations of OXPHOS disease.
Expected results
Arising from the work on the natural history of OXPHOS disease, a series of workshops will be organised,leading finally to the elaboration of guidelines for clinical management of OXPHOS patients and the evidence-based nosological reassessment of the entire field of OXPHOS disease. News about progress towards the objectives will be published and updated annually. Dissemination will be via existing clinical and patient organisation networks in the format of annual electronic newsletters. Major achievements of the project will be pre-published on the Eumitocombat website. All scientific results will be submitted for publication in high quality, peer-reviewed journals. During the lifetime of the project it is expected to elucidate novel gene defects causing OXPHOS disease, using linkage analysis. New tools for diagnosis of OXPHOS disease will be developed, based on retrovirus- and baculovirus-mediated complementation. New animal models are expected to be generated during the project. Procedures and tools for analysing the mtDNA maintenance machinery will be developed, including an improved procedure for the isolation of mitochondrial nucleoids. Each of the new treatment compounds to be developed will be characterised and tested in vitro. In the final conference/workshop organised by Eumitocombat the state of mitochondrial research will be evaluated, focusing on the evaluation of new treatment strategies at the patient level, arising from the outcomes of the project.
Calcium signal following loading with Rhod-2 and the hormone bradykinine in a control human fibroblast cell line
Aim
The projects main goals are to obtain a detailed understanding of the clinical and pathobiological consequences of OXPHOS disease in order to develop new treatment strategies. Efforts will be focused on complex I, complex IV, mitochondrial DNA maintenance and mitochondrial protein synthesis disturbances.The major objectives, around which the scientific and technological work is structured,apply to each of these disease categories: 1. to understand properly the natural history of the disease,its clinical manifestations and their time-course,and the relationship between genotype and phenotype. The eventual goal will be to provide routine and rapid diagnosis, which will form the rational basis for future therapy 2. to elucidate the pathophysiology of the disease by the analysis of biological models, thus revealing potential new therapeutic strategies or targets 3. to characterise in detail the cellular machinery primarily affected by the disease process (i.e. complexes I and IV, the components involved in their assembly, and the machinery of mtDNA maintenance and expression). A complete understanding of basic biological processes underlying OXPHOS will lead to the discovery of novel drug targets
The project sets out an ambitious, integrated research programme to build on the achievements described in the preceding section. Using many of the same tools and models, innovative, functional genomic technologies will be applied to define the cellular and organismal consequences of OXPHOS dysfunction and reveal pathways and molecules of potential value as drug targets. A definitive classification of OXPHOS disorders will be elaborated, using systematic clinical criteria and a rigorous application of genetics. Novel techniques will be developed for rapid diagnosis of mitochondrial disease based on functional complementation.The full panoply of genomic tools to identify the remaining key loci involved in OXPHOS disease will be applied. The consortium will combine their existing OXPHOS disease models and promising pharmacological agents to test out therapeutic strategies, in collaboration with SME partners. The aim for the four years of the project is to provide a platform for the development of effective treatments for OXPHOS disease that can have a real and sustained impact on the lives of patients and their families.
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RARE DISEASES
Coordinator
Prof. Smeitink, Jan Stichting Katholieke Universiteit University Medical Centre Nijmegen Nijmegen Center for Mitochondrial Disorders Department of Paediatrics Geert Grooteplein 10 P.O. Box 9101 6500 HB Nijmegen,The Netherlands Phone: +31 24 361 4430 Fax: +31 24 361 6428 Project web-site: http://www.eumitocombat.org Key words: rare diseases, inborn errors of energy metabolism, orphan diseases
Dr. Josef Houstek Institute of Physiology, Academy of Sciences of the Czech Republic Prof. Jiri Zeman Charles University, 1st Faculty of Medicine, Prague, Czech Republic Prof. Howard Jacobs University of Tampere, Institute of Medical Technology, Finland Prof. Robert Lightowlers, Dr. Douglas Turnbull University of Newcastle Upon Tyne, Department of Neurology, Newcastle upon Tyne, United Kingdom Prof. Ferdinando Palmieri, Prof. Luigi Palmieri University of Bari, Department of Pharmaco-Biology, Bari, Italy Dr. Agns Rtig, Dr. Pierre Rustin Institut National de la Sant et de la Recherche Mdicale, Paris, France Dr. Massimo Zeviani Istituto Nazionale Neurologico C. Besta, Milano, Italy
Partners
Dr. Peer Bork European Molecular Biology Laboratory, Structural and Computational biology, Heidelberg, Germany Dr. Jos A. Enriquez University of Zaragoza, Department of Biochemistry and Molecular Cell Biology, Spain Dr. Nib-Gran Larsson, Dr. Claes Gustafsson Karolinska Institute, Sweden Prof. Sir John Walker, Dr. Ian Holt, Dr. Michael Murphy Medical Research Council, Department MRC-Dunn Human Nutrition Unit, Cambridge, United Kingdom
Acronym: Eumitocombat Project number: LSHM-CT-2004-503116 EC contribution: 8 196 135 Instrument: Integrated Project Duration: 48 months Starting date: 01/07/2004
46
Euroglycanet
RARE DISEASES
Congenital disorders of glycosylation: a European network for theadvancement of research, diagnosis and treatment of a growing group of rare disorders
Summary
The congenital disorders of glycosylation (CDG) are an emerging group of inborn errors of metabolism. CDG are typically multisystem diseases, with a broad spectrum including mental retardation and severe developmental delay, structural abnormalities of the central nervous system and cardiac defects, malformations, hormonal deregulation and coagulation problems, peripheral neuropathies, etc. There is a high morbidity and a significant mortality. Euroglycanet will promote early diagnosis by offering the diagnostic tools for screening as well as for expert analysis and by raising awareness. It will integrate research activities in the field, and work towards the development of therapies for CDG and related disorders. To fulfil these aims, Euroglycanet will 1) develop and share effective tools for early and expert diagnosis; 2) manage a sample flow through the different laboratories involved in this activity and 3) maintain a database, accessible through Internet and a public website. Euroglycanet will also raise awareness by 4) providing information to the public and to physicians and other professionals, and by 5) offering training to expert clinicians and researchers in the field. To foster research it will select interesting cases for research and 6) establish an international research forum, including one international congress,where clinical and basic scientists will meet.The coordinated diagnostic and research activities include a.o. applications of DNAarrays, 2-D gels, mass spectrometry and capillary electrophoresis for the study of glycoprotein synthesis and defects. 7) The network will promote collaborations with companies for the development of therapeutics. The integration of clinical and basic research groups within the network is a strong advantage in this respect. Euroglycanet will also 8) increase quality and standardisation by offering QA schemes and 9) spread and promote access to diagnostic services by installing additional referral centres in different European countries, including the new member states. Distribution of Partners of the Euroglycanet project accross Europe
Problem
Glycosylation is the most complex type of biomolecule modification occurring in living organisms. Given this complexity and the large number of enzymatic steps involved in protein glycosylation, it is anticipated that many disorders are still unrecognised. Also,it is a rare disease, for which the diagnostic, clinical and research expertise is limited to a few centres in Europe. Most patients with CDG can be diagnosed by relatively simple laboratory tests that detect abnormal glycosylation in serum proteins. In contrast, the identification of the underlying defect often requires expert enzymatic, biochemical or molecular investigations. It is at this stage that the expert diagnostic services, offered by the different laboratories involved in the network, are playing an important role in the diagnosis of CDG.
Aim
Euroglycanet will bring together all the leading European groups with an interest and expertise in CDG and related syndromes.The aim is to co-ordinate research and expert diagnostic activities, and to promote awareness and knowledge of this group of diseases. The project also aims at providing the basic diagnostic tools for physicians by establishing referral laboratories in the European centers that collaborate with Euroglycanet. It will integrate research activities in the field, and work towards the development of therapies for CDG and related disorders. These research activities are grafted onto a central database and patient sample repository.The samples circulate along the different expert laboratories a principle which was coined carousel testing.
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RARE DISEASES
Expected results
1. unite the leading European groups into a multidisciplinary network 2. exploit novel diagnostic and scientific tools 3. continue the patient database and specific mutation databases 4. coordinate and expand a network of specialised centres that provide early and accurate diagnosis 5. develop new therapeutic strategies 6. raise awareness 7. training of young, expert clinicians and scientist and education of other specialists 8. quality assurance, quality assessment and standardisation
Coordinator
Prof. Matthijs, Gert Centre for Human Genetics, University of Leuven, Gasthuisberg, Herestraat 49 3000 Leuven, Belgium Phone: +32 16 34 60 70 Fax: + 32 16 34 60 60 Email: gert.matthijs@med.kuleuven.ac.be Project web-site: www.euroglycanet.org Key words: early diagnosis, patient database, awareness, training and education
Euroglycanet has identified national referral laboratories that will assume a role of satellites or outstations for the first-line analysis and dispatch of samples. All satellite laboratories from the network will be provided with the same technical equipment and standard test protocols. The network will provide access to (early) diagnostics at a panEuropean scale; it is committed to training and education, directly coupled to clinical and basic research. These activities will affect quality of life of the patients with CDG, and their families. A definitive diagnosis is one of the most important things for families with an affected child. The network will try to consolidate the European lead on clinical and fundamental research into this group of rare diseases. The close interaction between expert clinicians and specialised researchers, together with the centrally monitored carousel testing, could become a model for the organisation and integration of clinical and basic research for other rare diseases, in and beyond the metabolic field.
Partners
Assistance Publique-Hpitaux de Paris, France University of Nijmegen, the Netherlands University of Zurich, Switzerland Hospital Sant Joan de Du / IBC, Spain Institute of Child Health, London, United Kingdom University of Gttingen, Biochemie 2, Germany Eidgenssische Hochschule, Zurich, Switzerland Christian de Duve Institute of Cellular Pathology, Belgium INSERM U504,Villejuif, France Institute of Child Health,Athens, Greece University of Catania, Italy University of Porto, Portugal Childrens Memorial Health Institute,Warsaw, Poland University Hospital of Copenhagen, Denmark Charles University, Prague, Czech Republic Higher Medical School, Sofia, Bulgaria Universidad Autonoma de Madrid, Spain Hadassah and Shaare Zedek MC, Jerusalem, Israel Rambam Medical Center, Haifa, Israel Department of Paediatrics, Zagreb, Croatia Institute of Chemistry and Technology of Polymers, Catania, Italy Orphan Europe, Paris, France CLIMB, Crewe, United Kingdom Universittskinderklinik, Heidelberg, Germany
Acronym: Euroglycanet Project number: LSHM-CT-2005-512131 EC contribution: 1 200 000 Instrument: Coordination Action Duration: 48 months Starting date: 01/02/05
48
GENESKIN
RARE DISEASES
Rare genetic skin diseases: advancing diagnosis, management and awareness through a European network
Summary
Genetic skin diseases comprise almost 300 rare but often severe and even life-threatening diseases and syndromes. Despite recent identification of causative genes in a number of these disorders, the molecular bases of several others are still unknown, and often the function of the identified disease-gene products remains an unsolved mystery. In addition, disease number and rarity impair proper management, and no curative therapy is available. By bringing together clinicians, researchers and patient associations, GENESKIN aims to generate accessible knowledge and improve health care service structures for affected people.The focus is on five major disease categories: epithelial adhesion disorders, keratinisation disorders, ectodermal dysplasias, connective tissue diseases, DNA repair disorders. For each group, a clinical and laboratory network will generate and disseminate: 1) a list of reference centres with services offered, 2) diagnostic questionnaires/protocols, 3) gene cards, mutation database, diagnostic reagent lists, and ongoing clinical trial list. The research topics to be co-ordinated in GENESKIN deal with: i) improved early postnatal and pre-natal diagnosis by novel immunohistochemical/ biochemical and molecular tests, ii) identification of new genes involved in genetic skin diseases by collecting a sizeable number of biological samples, iii) definition of genotype-phenotype correlation and characterisation of newly identified gene product functions by creation of a sample databank. Knowledge dissemination and improved management will also be ensured through the organisation of involved personnel training. Finally, panEuropean communication among patients organisations, ethics committees, physicians and scientists will be promoted.The information regarding clinical/diagnostic protocols/lists, diagnostic and research tools and communication among different groups will be integrated and disseminated through a dedicated website.
Problem
Genetic skin disorders encompass almost 300 different diseases and syndromes, most of which are severely disabling or life threatening and have a major impact on health care services and personnel.The number and rarity of these disorders (prevalence between 1:6 000 and <1:500 000 for each condition) hamper single-centre (or country) studies aimed at their characterisation and cure. Despite the great progress of the last decade, the molecular basis of several of these diseases is still unknown, and in many cases the function of the known disease-gene products remains an unsolved mystery.Furthermore,no curative therapy is at present available for any form of genetic skin disease and pharmaceutical companies have limited or no interest in developing diagnostic and therapeutic strategies for these orphan diseases.A significant logistical problem is that only a few centres in Europe are in a position to try to deal with groups of these diseases and even then their expertise is limited to just a few specific conditions. Thus, expert knowledge for clinical and molecular diagnosis, for management and innovative therapy is isolated and scattered in an often uncoordinated way throughout Europe. As a result patients experience significant difficulties in finding experts and multidisciplinary healthcare teams specialised in clinical and molecular diagnosis, able to offer high quality disease management. This situation can only be overcome by a European mobilisation of activities and resources, most effectively through a European consortium that will facilitate development of substantially improved and cost-effective health care services.
Schematic representation of the GENESKIN project
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Aim
The present project arises as a joint effort of European scientists and clinicians, with the direct involvement of patients associations, to establish a consortium of groups engaged in providing a critical mass of patients and research tools in the fields of inherited skin diseases, including diseases predisposing to skin cancer. To this regard, the projects main objectives are: to create a European clinical and diagnostic network for five major groups of genetic skin diseases,namely epithelial adhesion disorders, keratinisation disorders, ectodermal dysplasias, connective tissue diseases, and DNA repair diseases to integrate, test and validate diagnostic and research tools for the above-mentioned disease groups to promote training on clinical, diagnostic and management aspects of specific disease groups to promote pan-European communication pathways among patients organisations, ethics committees, physicians and scientists.
function findings into clinical applications that are relevant to accurate, rapid and early diagnosis,molecular and prenatal testing,and to foster implementation of clinical trials. In particular, the multidisciplinary synergistic efforts of investigators and clinicians,in close collaboration with patient associations, will allow: the establishment of a European task force for the study of these rare disorders at fundamental and clinical levels; the rapid translation of the novel knowledge and diagnostic tools from the bench to the bedside, resulting in an improved diagnosis and management of these disorders at European and national scale; the augmentation of an early and accurate pre- and post-natal diagnosis, which is crucial for prognosis definition and proper management, and is beneficial for the psychological well-being of patients and families who do not feel well living in diagnostic uncertainty and insecurity; easier access for patients to clinical trials and in general earlier and proper management leading to an increase of the quality of life of the patients, and improvement of the clinical course of the disease. This will reflect positively over the duration of life expectancy and medical costs. In addition, close co-operation of physicians and scientists with public non-medical groups,i.e.patients organisations and ethics committees will contribute to: developing and maintaining an equal dialogue among these different parts; patient-specific needs being continuously part of medical and/or scientific decisions, in agreement with ethical values; further raising public awareness about rare diseases,fulfilling societal goals.
Expected results
a web-based informatics platform that, for each of the five categories of diseases listed above, will contain: 1) a list of reference centres with clinical/diagnostic services offered; 2) diagnostic questionnaires/protocols/check-lists; 3) gene cards and mutation database; 4) lists of available diagnostic reagents; 5) disease-related web-sites and ongoing clinical trials; 6) recent updates in the proper field. for selected diseases: 1) standardised immunohistochemical/ biochemical screening tests, preliminary to molecular diagnosis; 2) standardised prenatal and postnatal molecular diagnostic tests and a prototype assay based on microchip technology; 3) a virtual biological sample databank. dissemination of knowledge about clinical features, diagnostic procedures and management of specific disease groups at a European scale close alliance of patients organisations and ethics experts with physicians and scientists.
The achievement of the proposed objectives will greatly contribute to the implementation of the Community Policy Objective aimed at combating rare diseases. In fact, bypassing the problems related to the rarity of inherited skin diseases, the clinical and research network will provide a rapid translation of emerging gene discovery and gene
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Coordinator
Zambruno, Giovanna Provincia Italiana della Congregazione dei Figli dellImmacolata Concezione-I.D.I-I.R.C.C.S. Laboratory of Molecular and Cell Biology Via dei Monti di Creta 104 00167 Rome, Italy Phone: + 39 0666 464738 Fax: + 39 0666 464705 E-mail: g.zambruno@idi.it Project web-site: to be developed. Key words: rare genetic diseases, skin, dermatology, diagnosis
Centre National de la Recherche Scientifique, Laboratory of Genetic Instability and Cancer UPR 2169-CNRS Institut Gustave Roussy, Villejuif, France Hopital Necker Enfants Malades, Service de Dermatologie, Paris, France Consortium National de Recherche en Genomique, Centre National de Genotypage - Department of Dermatological Diseases, Evry, France Assistance Publique - Hpitaux de Paris Hospices Cantonaux - Centre Hospitalier Universitaire Vaudois, Service de Dermatologie des Hospices, Lausanne, Switzerland Universiteit Gent, Department of Medical Genetics, Ghent University Hospital, Belgium Erasmus Medical Center Rotterdam, Medical Genetic Cluster - Department of Cell Biology & Genetics, The Netherlands Academisch Ziekenhuis Gronigen, Department of Dermatology,The Netherlands Asociacion de Epidermolisis Bullosa de Espana, Consejo Superior de Investigaciones Cientificas, Centro Nacional de Biotecnologia, Departamento de Immunologia y Oncologia, Madrid, Spain Federal Academic Hospital of Feldkirch, Department of Dermatology, Austria Gemeinnutzige Salzburger Landeskliniken Betriebsgesellschaft mbH, Dermatology - Laboratories, Salzburg, Austria Department of Dermato-Venereology Semmelweis University, Budapest, Hungary Department of Medical Sciences /Dermatology and Venereology, University Hospital, Uppsala, Sweden Uppsala Universitet, Department of Medical Sciences Dermatology and Veneralogy Uppsala, Sweden
Partners
Consiglio Nazionale delle Ricerche, Rome, Italy Department of Biomedical Sciences, Universit di Modena e Reggio Emilia, Modena, Italy Department of Dermatology, University Hospital, Freiburg, Germany Department of Dermatology, University of Munster, Germany Centre for Functional Genomics, University of Cologne, University Hospital, Cologne, Germany Philipps-Universitaet Marburg, Institut fuer Allgemeine Humangenetik, Marburg, Germany Genetic Skin Disease Group, King's College, London, United Kingdom Centre for Cutaneous Research, Queen Mary & Westfield College, University of London, United Kingdom Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom Cancer Sciences and Molecular Pathology, University of Glasgow, United Kingdom DebRA Europe, Crowthorne, United Kingdom Our Ladys Hospital for Sick Children, Department of Paediatric Dermatology, Dublin, Ireland Institut National de la Sant et de la Recherche Mdicale, INSERM Units 634, 563 and 217, Nice, France Centre Hospitalier Universitaire de Nice, Service de Dermatologie, Nice, France
Acronym: GENESKIN Project number: LSHM-CT-2005-512117 EC contribution: 1 238 199 Instrument: Coordination Action Duration: 36 months Starting date: 01/07/2005
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EuroWilson
Wilson Disease: Creating a European clinical database and designing multicentre randomised controlled clinical trials
Summary
Wilson Disease is genetic disorder in which deficiency of a coppertransporting P-type ATPase leads to intracellular retention of copper in the liver, brain, and kidney. Incidence estimates vary from 1/30 000 to 1/100 000. There is controversy as to treatment, because of a lack of randomised trials comparing copper-chelators such as penicillamine or trientine with zinc. In preparation for the planning of such trials, a European Clinical Database is to be established. This will inform us as to the incidence of the disease, its geographical variation, and the frequency of its differing clinical presentations. sulfate (1961), and trientine (1969) were major therapeutic advances. We now know it to be a disorder of a P-type ATPase situated in the trans-golgi,ATP7B, which is a copper transporter. Its deficiency leads to impaired biliary excretion of copper, impaired caeruloplasmin synthesis, and copper accumulation in the liver, the basal ganglia of the brain, and proximal renal tubules.The clinical manifestations are diverse. Liver disease is the most frequent presentation in children, and may be of different types and severity. Some present with acute liver failure with encephalopathy, requiring urgent transplantation. Some have a more gradual onset resembling a chronic hepatitis, while other may be discovered to have cirrhosis with few symptoms. Haemolysis is frequently also found. By contrast, older patients tend to present with neurological difficulties. Abnormalities of speech, coordination and fine motor performance progress to severe tremor, movement disorder and disability. Other organs are affected to a variable degree,resulting in joint symptoms,renal disease,and anaemia. Pre-symptomatic patients are detected through family studies. Older patients with neurological disease tend to have the common H1069Q mutation. However, there is great phenotypic variability amongst patients with the same genotype, and the reasons for this are not known.
Problem
It is almost exactly 100 years since Wilson described the neurological and liver disorder which bears his name. It was recognised to be autosomal recessive in inheritance in 1921, and to be associated with copper storage in 1945. The discovery of penicillamine (1953), zinc
The trans-Golgi P-type ATPase, with its 8 transmembrane sections
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Members of the consortium at a meeting in September 2004
There is a need to determine an optimum treatment regime. A Cochrane style evaluation of the current literature on Wilson Disease and treatment yielded over 1000 hits. Over 500 articles were expert opinions in favour of either zinc treatment or the use of copper chelators. No randomised clinical trial could be found, and less than
20 articles described the results of a particular treatment in a series of patients. In only one article, describing 58 patients, both treatment options (zinc and D-penicillamine) were evaluated in a nonrandomised way. As no strict end points were defined no firm conclusions could be drawn.
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Aim
The principal aim of this project is to establish a European Clinical Database of newly presenting patients with Wilson Disease. The Kayser-Fleischer (KF)ring, copper deposit in Descemets membrane in the eye.
Expected results
We will determine: 1. the overall incidence of Wilson Disease, and its variation in different countries.There is an impression of increased incidence in, for example, Sardinia, but this may be because of better ascertainment; 2. the numbers of patients in different clinical categories; 3. the treatment regimes currently being used and their short-term outcomes; 4. the genotype of newly presenting patients. From this data, the feasibility of a randomised trial will be assessed. Phenotypic heterogeneity implies that this will either be a stratified trial, or a series of trials of homogeneous subsets.
Additional benefits
1.The project will bring a profile to a rare disease, provide patient and physician information, and stimulate related research. 2.A quality assurance scheme will be established amongst the participating molecular diagnostic laboratories. 3.The discussions between clinicians about database items are yielding a valuable consensus about physical sign assessment in Wilson disease, and potentially other disorders. 4. Continuation of the database will provide a long-term research resource. 5.The data collection system will be useful for other multicentre studies.
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Coordinator
Prof.Tanner, Stuart Academic Unit of Child Health University of Sheffield Childrens Hospital Western Bank S10 2TH Sheffield, United Kingdom Phone: +44 114 271 7303 Fax: +44 114 275 5364 E-mail: m.s.tanner@sheffield.ac.uk Project web-site: www.eurowilson.com Key words: copper, liver, cirrhosis, movement disorder, database, randomised trial
Dr Loudianos, Georgios Dipartimento di Scienze Biomediche e Biotecnologie Cagliari, Italy Dr Schmidt, Hartmut Med Klinik m.S. Gastroenterologie, Hepatologie, Charite Universitatsmedizin Berlin Berlin, Germany Dr Melter, Michael Pediatric Gastroenterology, Hepatology and Liver Transplanatation Hannover Medical School Hanover, Germany Dr Houwen, Roderick Department of Pediatric Gastroentrology Utrecht,The Netherlands Prof. Cohen, Olivier HC Forum, Equipe Genome Laboratoire TIMC Medical School of Grenoble La Tronche, France Mrs Parker, Samantha Medical and Marketing Department Orphan Europe Sarl Paris-La Defense, France Prof. Sarles, Jacques Service de Pediatrie Multidisciplinarire Hopital denfants de la Timone Marseille, France Dr Dhawan,Anil Division of Hepatology and Transplantation Institute of Liver Studies Kings College London London, United Kingdom
Partners
Prof. Czlonkowska,Anna 2nd Department of Neurology Institute of Psychiatry & Neurology Warsaw, Poland Dr Socha, Piotr Dept. of Gastroentology, Hepatology The Childrens Memorial Health Institute Centrum Zdrowia Dziecka, Warsaw, Poland Dr Szonyi, Laszlo 1st Department of Paediatrics, Semmelweis University Budapest, Hungary Prof Ferenci, Peter Dept. Of Internal Medicine Medizinische Universitat Wien AKH Wien,Vienna,Austria Prof. Deutsch, Johann Medizinishe Universitat Graz Univ Klinik fur Kinder and Jugendheilkunde Graz,Austria Prof.Vegnente,Angela Department of Paediatrics, University "Federico II" Naples Naples, Italy
Acronym: EuroWilson Project number: LSHM-CT-2004-503430 EC contribution: 799 645 Instrument: Coordination Action Duration: 48 months Starting date: 01/06/04
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PWS
Prader-Willi Syndrome: A model linking gene expression, obesity and mental health
Summary
Prader-Willi syndrome is a rare neurodevelopmental disorder with a characteristic physical and behavioural phenotype that results from the absence of expression of as yet unidentified maternallyimprinted/ paternally-expressed gene(s) at 15q11-13. Seven maternally-imprinted genes have been located in the PWS critical chromosomal region and in the mouse homologues. HBII-52 and HBII-85 in humans, Magel 2, and Necdin are four candidates that will be the focus for developing mouse models in order that genotype/phenotype relationships and signalling pathways can be studied. Hypothalamic tissue obtained at post-mortem from people with PWS will also be used to investigate hypothalamic pathways known to be important in the control of eating behaviour.The basis for a European-wide clinical study of developmental outcomes in PWS will be established through the development of a clinical database and its evaluation in specific EU countries. The mouse 7C chromosomal region has conserved synteny with the human 15q11-q13 region. Four potential mouse models with a global deficiency of paternal gene expression in the 7C chromosomal region, and therefore potential models for PWS, have been described. The observed phenotype is consistent with the feeding difficulties and failure to thrive that is characteristic of PWS infants.Thus, complex mouse models provide the means for investigating protein interactions and signalling pathways linking gene expression to observed behaviours. The power of clinical studies of PWS at national levels are limited because of the relative rarity of the syndrome. Clinical studies that include sufficient numbers of people with PWS of different genetic sub-types of both genders across all ages are required to determine influences on developmental outcomes.
Aim
1.To establish specific mouse models of PWS in order to investigate genotype/phenotype relationships and signalling pathways; 2. to investigate hypothalamic feeding pathways using post-mortem tissue from people with PWS; 3.to establish the basis for a European-wide clinical study investigating influences on developmental outcomes for people with PWS.
Problem
Prader-Willi syndrome is a complex neurodevelopmental disorder resulting from absent expression of maternally imprinted/paternally-expressed, but as yet unidentified, gene(s) at the locus 15q11-13.The two most common genetic sub-types are chromosomal deletions at 15q11-13 involving chromosome 15 of paternal origin and chromosome 15 uniparental maternal disomies. Two other rare genetic abnormalities are also described.The PWS phenotype in infancy is characterised by extreme hypotonia, failure to thrive, hypogonadism, and the need for augmented feeding. From approximately two years of age, excessive eating becomes apparent, remaining throughout life and if left unchecked, leads to severe obesity and early death. Other diagnostic characteristics include developmental delay, mild intellectual disabilities, short stature, small hands and feet, and delayed sexual development, together with a propensity to other maladaptive behaviours. This over-eating behaviour is due to an abnormal satiety response to food intake. In adult life those with PWS due to chromosome 15 maternal disomy invariably develop severe affective psychotic illness. Studies on post-mortem-obtained hypothalamic tissue have shown a reduction in oxytocin expressing neurones of the hypothalamus. So far the function of only two of the hypothalamic peptides important in the regulation of appetite have been investigated and in these two cases no abnormalities have been found (NPY and agouti-related peptide).
Expected results
1.The development of a complex mouse model and four specific knockout mouse models of PWS. 2. Full investigation of genotype/phenotype relationships in the specific mouse models and of the biological functions of the genes and the associated protein interaction networks and signalling pathways. 3. Investigation of specific hypothalamic feeding pathways in human hypothalamic tissue obtained at post-mortem from people with PWS. 4.The establishment of a clinical database compatible with ethical and clinical practice throughout the EU for the collection of clinical and research data on people of all ages with PWS. 5.The assessment of the database in different European settings. 6.The integration of data from mouse, human hypothalamic investigations and existing clinical studies in PWS to inform obesity and behavioural research more generally.
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For people with PWS and their families it is this extreme propensity to over-eating and other associated behavioural and psychiatric problems that has the most significant detrimental effect on their quality of life and on life expectancy. Understanding the mechanisms in PWS that link genotype to phenotype has the potential to result in new treatments and will provide models for obesity and psychiatric research more generally.The main focus of this project is on basic science research but results from subsequent clinical studies on developmental outcomes will make possible the integration of basic science and clinical data leading to the development of more sophisticated models linking the abnormal expression of imprinted gene(s) to developmental processes and specific behavioural and physical outcomes.
Coordinator
Prof. Holland,Tony Section of Developmental Psychiatry Department of Psychiatry University of Cambridge 18b Trumpington Road Cambridge, CB2 2AH, United Kingdom Phone: + 44 1223 746112 Fax: + 44 1223 746122 E-mail: ajh1008@cam.ac.uk Project web-site: to be developped Key words: Prader-Willi Syndrome, genomic imprinting, hypothalamus, obesity
Partners
CNRS/Institut de Biologie du Developpement de Marseille-Luminy/UMR 6256, Marseille, France Katholieke Universiteit Leuven, Leuven, Belgium Section of Biological Developmental Psychology, University of Maastricht,The Netherlands Institut fur Humangenetik, Universitat Duisburg-Essen, Essen, Germany Netherlands Institute for Brain Research,Amsterdam, The Netherlands Department of Womens and Child Health, Karolinska Institute, Stockholm, Sweden Department for Functional Genomics, University of Innsbruck,Austria Weizmann Institute of Science, Rehovot, Israel HC Forum, Grenoble, France Centre Europen de la Recherche en Biologie et en Mdecine
Acronym: PWS Project number: LSHM-CT-2005-512136 EC contribution: 1 655 342 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/12/2005
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EUGINDAT
European genomics initiative on disorders of plasma membrane amino acid transporters

Summary
The project EUGINDAT is an integrated approach that links genetics, biochemistry, physiology, genomics, proteomics, structural biology, drug development and clinical studies in an attempt to improve understanding and treatment of Primary Inherited Aminoacidurias (PIA). PIA are rare diseases involving defects in renal reabsorption of amino acids that also affect other organs.The project applies three main technological avenues to the study of PIA: I) clinical and genetic characterisation of PIA; II) functional genomics of renal reabsorption of amino acids; III) structural biology of PIA-associated amino acid transporters.Moreover,the present developments in the clinics and the molecular bases of two of these diseases (Cystinuria and Lysinuric protein intolerance [LPI]) allows the application of this knowledge to unravel the pathophysiological mechanisms of these diseases and to test new therapeutic strategies. (IG) and unlabeled aminoacidurias. The proposal aims to study new candidate genes for cystinuria, DA, HDis and IG. 2. to gain a thorough knowledge of the molecular structure of relevant transporters using 2D crystals of prokaryotic, and eventually eukaryotic homologues and 3D crystals of water-soluble extracellular domains. 3. to complete a functional genomic study of relevant transporters underlying PIA and renal reabsorption of amino acids at three levels: i) identification of transporters with a role in the transepithelial transport of amino acids in the proximal tubule OK cell model, ii) generation of KO mice,and iii) identification of polymorphisms (SNPs) in renal transporters that show association with renal reabsorption of amino acids in genetically isolated human populations. 4. to identify genes and/or loci that affect cystinuria lithiasis, and may eventually explain gender-related and individual variability in stoneforming activity in patients with cystinuria. 5. to develop new therapeutic strategies for cystinuria lithiasis. 6. to identify the mechanisms contributing to the pathology of LPI which explain the hepatic phenotype (hyperammonemia) and the immune system-compromising symptoms. 7. to test new therapeutic approaches for the life-threatening complications of LPI.
Problem
PIA are rare disorders of amino acid transporters expressed in the plasma membrane of renal epithelial cells that impair tubular and intestinal absorption of amino acids,and that may also affect other organs and produce severe clinical consequences. These are rare or orphan diseases. The orchestrated way in which the various amino acid and peptide transporters in renal apical and basolateral membranes allow efficient renal reabsorption of filtered amino acids and provide amino acids for the needs of the cells is far from being completely understood.
The integrated knowledge to be acquired on PIA within EUGINDAT will result in: a) deep clinical and genetic description of PIA, including very rare forms of these diseases (PIA-DATABASE); b) generation of a new picture of the physiology and pathophysiology of the cellular handling of amino acids in the mammalian kidney. Moreover, with the capability of crossing animals with defects in individual genes to obtain multiple knock-out lines a unique European competence area on renal amino acid transport processes is created. c) EUGINDAT also takes its
Aim
The EUGINDAT project has two main goals: the first is, to improve our understanding of the genetic, molecular, cellular and physiological basis of PIA. The key goal of the basic science part of EUGINDAT is the most comprehensive understanding of the inherited aminoacidurias by analysis of the patho-physiological processes down to individual proteins and genes followed by a systematic reintegration of the knowledge gathered to the most complex level of the organisms. The second goal is to explore new strategies for the diagnosis and therapy of these diseases, including improved patient care based on the knowledge generated in the project.
Expected results
1. to complete a clinical and molecular-genetic description of PIA with the generation of a European PIA-DATABASE including: Cystinuria, Lysinuric Protein Intolerance (LPI), Dicarboxylic Aminoaciduria (DA), Hartnup Disorder (HDis), Iminoglycinuria Chimeras used to generate the LAT-2 knock-out mouse model
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world-recognised expert knowledge and its technological capabilities to work on the carrier protein structures,which represents an added value as this area has traditionally been solely in the hands of biochemists, physicist or chemists. The 3D structure of amino acid and peptide transporters related to PIA and nutrition will provide the basis for the understanding of the malfunctions of the proteins based on sequencedependent conformational alterations in substrate binding and transport capability and protein stability. d) Finally, information gained on PIA diseases is being transferred into development of new drug and therapeutic approaches for Cystinuria and Lysinuric protein intolerance.
Coordinator
Dr Palacn, Manuel Universitat de Barcelona Facultat de Biologia Department de Bioqumica y Biologia Molecular Avgda. Diagonal, 645. Edifici Nou. Planta 1 08028 Barcelona, Spain Phone: +34 93 403 4617- Fax: +34 93 402 1559 Email: mpalacin@porthos.bio.ub.es Project web-site: http://www.ub.edu/eugindat Key words: amino acids, transporters, primary inherited aminoacidurias, Cystinuria, Lysinuric protein intolerance, Dicarboxylic aminoaciduria, Hartnup disorder, Iminoglycinuria, genomics, structural studies, knock-out models.
Partners
Dr Orozco, Modesto Universitat de Barcelona Facultat de Qumica Dept Bioqumica y Biologia Molecular (Biologia) Barcelona, Spain Prof. Daniel, Hannelore TU Mnchen Wissenschaftszentrum Weihenstephan Institut fr Ernhrungsphysiologie Freising-Weihenstephan, Germany Dr Nunes,Virginia Centro de Gentica Mdica y Molecular Institut de Recerca Oncologica (IRO) Hospital Duran i Reynals Spain Dr Gasparini, Paolo Fondazione Telethon Rome. Italy Prof. Sebastio, Gianfranco Professore Associato di Pediatria, Universit Federico II Naples, Italy
Dr Fotiadis, Dimitrios Maurice E. Mller Institute at the Biozentrum, University of Basel Basel, Switzerland Dr. Kanner, Baruch The Hebrew University of Jerusalem Jerusalem, Israel Huoponen, Kirsi University of Turku, Department of Medical Genetics Turku, Finland Dr. Simell, Olli University of Turku, Department of Pediatrics Turku, Finland Dr Wagner, Carsten Institute of Physiology, University of Zurich Zurich, Switzerland Prof.Verrey, Franois Institute of Physiology, University of Zurich Zurich, Switzerland Prof. Borsani, Giuseppe University of Brescia, School of Medicine Department of Biomedical Sciences and Biotechnologies Brescia, Italy Prof. Lang, Florian Department for Physiology, University of Tubingen Tubingen, Germany Dr Della Strogalo, Luca Head Dpt. Of Nephrology and Urology Childrens Hospital and Research Institute Bambino Ges Rome, Italy Dr Bisceglia, Luigi IRCCS Casa Sollievo della Sofferenza, Servizio di Genetica Medica San Giovanni Rotondo (FG), Italy Dr Pras, Elon Institute of Human Genetics Sheba Medical Center, Israel Dr Rubio, Guillermo Laboratorios Rubi, S.A Castellbisbal, Spain Dr Grosse, Johannes Ingenium Pharmaceuticals AG Director Bussines Development, Program Partnering Martinsried, Germany
Acronym: EUGINDAT Project number: LSHM-CT-2003-502852 EC contribution: 3 050 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/03/2004
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EURAPS
Autoimmune polyendocrine syndrome type I a rare disorder of childhood as a model for autoimmunity
Summary
Autoimmune polyendocrine syndrome type I (APS I; OMIM 240300), a rare genetic disorder of childhood with autoimmune reactions against a range of different tissues, has been shown to be an invaluable tool in understanding autoimmune reactions. APS I is characterised by autoantibodies against several defined autoantigens often identical to those found in common autoimmune disorders such as type 1 diabetes mellitus.The cellular and molecular mechanisms leading to this complex syndrome remain, however, incompletely understood. Studies on recently generated animal models for the disease, as well as genomicwide approaches to identify immune-modulating genes, will provide novel information of importance not only to the patients affected with this rare disorder, but will also increase our understanding of the pathogenesis of autoimmune diseases in general. an early age with both endocrine and non-endocrine tissues affected, and in addition, mucocutaneous candidiasis that is often a hallmark of the disease. APS I is more common in certain areas, such as Finland (prevalence 1/25 000) and Sardinia.A number of autoantigens have been identified in APS I.These discoveries have provided diagnostic tools and predictive markers for the appearance of various clinical components of the disease. Furthermore, some of the autoantigens identified in APS I have later been shown to be of importance in more common autoimmune disorders. The AIRE gene product is most prominently expressed in the medullary epithelial cells of the thymus. Thymic medullary epithelial cells are involved in the negative selection of lymphocytes during the lymphocyte maturation process in the thymus. An analysis of the cellular and functional consequences of different missense mutations of the AIRE gene product has allowed a detailed mapping of the various functional domains of the protein. Several lines of Aire -/- mice have been generated providing an excellent animal model for the disease.Despite these recent advances,the physiological function of AIRE or the mechanisms responsible for autoimmunity when AIRE is defective are not yet fully understood. The reason for the mucocutaneous candidiasis infection occurring in almost all patients remains completely obscure.
Problem
APS I (OMIM 240300), also known as APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) is an autosomal recessive disorder caused by mutations in the AIRE gene on chromosome 21. Patients develop the first symptoms of the disease at
Aim
The first objective is to use this disorder as a model to understand the immunological mechanisms at a molecular level that predispose to autoimmunity and to the propensity to develop fungal infections. The second objective is to provide better care of patients with APS I by developing new diagnostic tests, revising the diagnostic criteria, and improving the understanding of the clinical course and the longterm complications.
Embryonic thymus day 13 of gestation. Cortical epithelial cells are stained in green for Keratin 8, medullary epithelial cells to be are stained in pink for cytokeratin 5 and MTS10 cell antigen
Expected results
1. Establishment of a pan-European database and biobank for APS I patients. 2. Increased awareness of the disease among physicians and dissemination of knowledge about recommended follow-up procedures and diagnostic and therapeutic options. 3. Define the function of the AIRE gene product in thymic T cell development and in the establishment of tolerance.
Staining of Paneth cells (producing defensins and enzymes important to the host defence against bacterial, fungal and viral infections) in the small intestine using a serum from a patient with autoimmune polyendocrine syndrome type 1.
4. Identification T cell and B cell epitopes of defined autoantigens. 5. Discovery of genes that modify the intensity and/or course of APS I. 6.A collection of expression profile data from cells and tissues with a normal or defective AIRE to identify targets regulated by AIRE. 7. Elucidation of the mechanisms underlying the propensity to develop mucocutaneous candidiasis.
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Identification of modulating genes for the disease, of factors in the upstream regulation of AIRE gene expression and of proteins down-stream regulated by the AIRE gene product,will all undoubtedly help in identifying important drug targets for the modulation of various immune reactions. Also,the discovery of novel autoantigens will improve the clinical followup of APS I patients and may be of value in the diagnosis of other autoimmune disorders not associated with APS I.Moreover,clarification of the mechanisms underlying the propensity to develop mucocutaneous candidiasis can lead to novel therapeutic possibilities. Lund, Sweden Prof. Husebye, Eystein S. University of Bergen Endocrinology unit, Institute of Medicine Bergen, Norway Prof. Manns, Michael P. Medizinische Hochschule Hannover Department of Gastroenterology, Hepatology and Endocrinology Hanover, Germany Prof. Palmer, Ed University Hospital Basel Basel, Switzerland Prof. Peltonen, Leena National Public Health Institute Department of Molecular Medicine Helsinki, Finland Prof. Peterson, Prt University of Tartu, Institute of General and Molecular Pathology Tartu, Estonia Prof. Romani, Luiginia University of Perugia, Department of Experimental Medicine and Biochemical Sciences Perugia, Italy Prof. Samaranayake, Lakshamn P. University of Hong Kong Department of Oral Microbiology, Faculty of Dentistry Hong Kong, China Prof.Weetman,Anthony P. University of Sheffield, Division of Clinical Sciences Clinical Sciences Centre, Northern General Hospital Sheffield, United Kingdom Prof. De Virgiliis, Stefano University of Cagliari, Dipartimento di Scienze Biomediche e Biotecnologie Laboratorio di immunologia e genetica molecolare, Clinica Pediatrica Cagliari, Italy Prof. Scott, Hamish S. Walter and Eliza Hall Institute Genetics and Bioinformatics Division Parkville, Australia
Coordinator
Prof. Kmpe, Olle Uppsala University Department of Medical Sciences University Hospital 75185 Uppsala, Sweden Phone: + 46 186 112 978 Fax: + 46 185 25795 E-mail: olle.kampe@medsci.uu.se Project web-site: http://www.molecularmedicine.se/EURAPS Key words: rare disorders, autoimmunity, polyendocrinopathies; thymus, disease models,
Partners
Prof. Betterle, Corrado University of Padua Department of Medical and Surgical Sciences, Endocrine Unit Padua, Italy Prof. Cahill, Dolores Royal College of Surgeons in Ireland Dublin, Ireland Prof. Cerundolo,Vincenzo University of Oxford, Department of Medicine,Tumour Immunology Unit The Weatherall Institute of Molecular Medicine Oxford, United Kingdom Prof. Goodnow, Christopher C. The Australian National University Medical Genome Centre, John Curtin School of Medical Research, Canberra,Australia Prof. Hollnder, Georges University of Basel, Pediatric Immunology Department of Clinical-Biological Sciences Basel, Switzerland Prof. Holmdahl, Rikard Lund University, Department of Cell and Molecular Biology
Acronym: EURAPS Project number: LSHM-CT-2005-005223 EC contribution: 3 000 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/05/2005
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AUTOROME
From immune responses in rare autoimmune diseases to novel therapeutic intervention strategies a personalised medicine approach
Summary
Rare autoimmune diseases are chronic inflammatory diseases affecting a large number of the European population. Chronic inflammation leading to destruction of target organs results in disability and enormous human suffering and to large socio-economic costs. Therefore, understanding its pathogenesis constitutes an R&D area of strategic importance, both, scientifically and also socio-economically. This proposal integrates leading groups with state-of-the-art resources and projects from academia and SMEs by creating a critical mass sufficient to promote R&D interactions between basic and applied science.The work will lead to a better understanding of mechanisms that contribute to rare autoimmune diseases and provide us with leads for improved diagnostics and therapeutics. by profiling autoantigens and autoantibodies and determine the major autoreactive epitopes by addressing mechanisms that determine the initiation,progression and chronicity of the humoral immune response on the cellular level (T-cells,APC cells, B-cells, epithelial cells) by characterising cellular differentiation, maturation and migration processes with a strong focus on B cell development, making use of animal models by developing therapeutic approaches to eliminate autoantibodyproducing cells. Novel human and murine autoantigens will be characterised and epitope and paratope mapping will be performed. Peptide and autoantigen filters/chips will be validated in concert with clinical partners leading to diagnostic kits. Anti-idiotypic antibodies will be analysed from intravenous immunogloblulin fractions (IVIG).Idiotypic peptides and therapeutic antibodies are generated and validated in functional assays as well as in animal models. Cell types and differentiation steps of the cellular immune system are studied in different mouse models.This analysis is complemented by FACS sorted cellular blood components derived from diseased patients to be studied in depth on the transcriptome and proteome level in order to functionally analyse molecular parameters found in rare autoimmune diseases under study.
Objectives
Rare autoimmune diseases e.g. various subtypes of systemic vasculitis, are associated with substantial morbidity and even accelerated mortality in affected persons (children and elderly). In many cases these diseases are systemic,inflammatory,progressive,chronic and destructive diseases affecting numerous organs and tissue types.These diseases are associated with pain, and various organ manifestations (entitled syndromes) leading to organ failures and final death. One of the hallmarks of rare systemic autoimmune diseases is the formation of autoantibodies driving the pathology of the disease.These autoantibodies are directed e.g. against negatively charged phospholipids as in the anti phospholipid syndrome (APS), against components of the nucleus such as DNA, RNA, histones, nuclear proteins and proteinnucleic acid complexes as in SLE and against nuclear components like centromer antigens or topoisomerase I as in systemic scleroderma (SSC).As of yet it is not clear how the different autoantibodies contribute to the organ specific pathologies of the various diseases. Neither clearcut diagnostics and prognostics nor specific therapeutics ultimately leading to a cure of the disease are available.
Work packages
AUTOROME is dedicated to improve the current stateof-the-art methodology in the understanding of aetiology, pathophysiology, progress and therapy of rare autoimmune diseases by conducting the following work packages:
Project overview
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Expected results
Comprehensive technology platforms (including protein chips, mass spectrometry, phage libraries, immunoscoping) will be employed to identify autoantibodies, autoantigens and epitopes contributing to disease initiation, progression and chronicity. The rationale of novel therapeutic strategies depending on the generation of anti-idiotypic peptides and therapeutic antibodies as well as siRNA constructs will be evaluated. In a personalised manner pathogenic B cells and plasma cells will be targeted related to the disease parameters found in individual patients determined by spectratyping and mass spectrometric autoantibody characterisation.Expected achievements and deliverables of this proposal are likely to also help to elucidate molecular mechanisms in immune processes and autoimmune diseases in general and will,therefore,be of broad scientific and socio-economic value. Specific expected results are: identification of novel autoantigens and immuno-dominant epitopes in rare autoimmune diseases identification of immune cell subsets associated with rare autoimmune diseases description of autoantibody profiles specific for individual patients, specific diseases and in animal models identification of novel target genes in rare autoimmune diseases elucidation of synthetic autoreactive peptides and siRNAs for the development of specific modulators of the pathogenic humoral immune response development of diagnostic tools to assess disease severity and to predict disease onset detailed characterisation of human B cell development and selection elucidation of autoimmune pathways and therapeutic approaches using mouse models improved understanding of the immunopathology of autoimmune diseases Finally, prognostic markers and diagnostic tools should lead to individualised therapeutic approaches using idiotypic peptides as well as therapeutic antibodies and siRNA. Synthetic peptides will be generated and applied for the following aims: 1) to develop an ELISA kit for detection of autoAbs specific for thrombosis-associated pathogenic epitopes in order to predict thrombotic risk or recurrent fetal loss in patients having these specific autoAbs; 2) to neutralize the biological activity of the studied autoAbs, in vivo and in vitro; 3) to induce specific B cells apoptosis of the pathogenic autoAbs secreting cells.
Diagnostic tools assessing the relevance and distribution of pathogenic antibodies in individual patients are one essential milestone in generating and selecting appropriate therapeutic interventions strategies.The generation and administration of anti-idiotypic peptides interfering with pathogenic antigen-antibody interactions is one way to help patient suffering from severe autoantibody-mediated autoimmunities.The analysis of autoimmune diseases might become a leading force on the way to more personalised therapeutic strategies and prevention. Reducing the incidence, prevalence and severity of autoimmune diseases consequently relieves the economic and social impact on health-care costs for any society.
Coordinator
Prof.Thiesen, Hans-Jrgen Institute of Immunology University of Rostock Schillingallee 70 18055 Rostock, Germany Phone: +49 381 494 5870 Fax: +49 381 494 5882 Email: hans-juergen.thiesen@med.uni-rostock.de Project web-site: http://www.autorome.de Key words: anti-idiotypic; anti-phospholipid syndrome (APS); autoimmune lymphoproliferative syndrome (ALPS); autoimmunity; autoantigen; autoantibody; systemic lupus erythematosus (SLE); systemic scleroderma; systemic vasculitis
Partners
2 France 3 Denmark 3 Switzerland 1 Ireland 1 Israel 1 The Netherlands
Acronym: AUTOROME Project number: LSHM-CT-2004-005264 EC contribution: 2 700 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/11/2004
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Orphanplatform
A European platform of integrated information services for the coordination of rare disease research in Europe, with various stakeholders from research, SMEs and patient organisations and the coordination of early clinical trials
Summary
The project aims at developing information tools to address in a comprehensive and integrated approach the set of factors that currently affects research on rare diseases and its coordination.The specific objectives are: (1) to develop an information service, freely accessible on the Internet, dedicated to research activities in the field of rare diseases and orphan medicinal products, including a database of research projects, funded at MS level and at the EU level, and a database of collections and research networks;(2) to develop services aiming at speeding up the enrolment of patients in clinical research; (3) to develop a database of research projects with development potential, to help scientists and industry establish the necessary partnerships; (4) to organise a workshop with all stakeholders to discuss identified bottlenecks and find solutions.This project is based on input from the following (1) an EU-funded information service on rare diseases: Orphanet (www.orpha.net); (2) a European platform of patients organisation, science and industry (EPPOSI) which actively supports partnering activities; (3) an umbrella organisation of patient support groups (Eurordis) involved in supporting research and regulatory activities.The project aims at establishing the platform of services in 11 European countries in the pilot phase in order to propose an extension to the 25 European countries within two years. Ultimately, the goal is to convert scientific developments into diagnostic tools and therapies as quickly as possible. Patients suffering from such conditions should benefit from the same quality of treatment as other patients. Treatment of the very small number of patients affected by a specific rare disease results in fragmentation of research efforts and limited potential for commercial development of medicinal products. Therefore it is essential to act at a European level. The Fifth Framework Programmes for Research and Technological Development has supported research on rare diseases, to promote the establishment of cross-national cooperation.The EU gives priority to rare diseases within the new EU public health framework.The EU Regulation on Orphan Medicinal Products (OMP) was adopted in order to stimulate prevention and development of new diagnostic tools, and therapies for rare diseases. It is highly effective. Several Member States have taken initiatives to support research in the field of rare diseases. France, Germany, Ireland and Spain have set up specific programmes to support networking activities. France, Germany,Spain,Italy and the Netherlands have established committees to review research activities and advise on research issues at the governmental level.Several charity organisations are strongly involved in the field, especially the French and Italian Telethons.
Problem
Over 20 million Europeans are affected with rare diseases.Almost all these rare diseases are life-threatening or chronically debilitating disorders and most of them are genetic.To date, 5000 to 8000 phenotypes have been described among which 2000 are already assigned to one or several genes. Rare diseases are of the utmost importance in terms of both public health and scientific challenge as they are due to the failure of unique physiological pathways.Moreover,rare diseases represent an experimental model of normal cellular and tissular function of cells and contribute to a better understanding of more common diseases as well as paediatric diseases.
The Orphanplatform website
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Aim
The project aims to develop information tools in order to address in a comprehensive and integrated approach the set of factors that currently affects research on rare diseases and their validation at European level. Ultimately, the goal is to convert scientific developments into therapies as quickly as possible and to ensure timely access to innovative practices, tools and medicines.
3) Availability of OrphanXchange, a marketplace of research projects of potential interest for biotech and pharma industry.This service is expected to contribute significantly to the transfer to the market of innovative therapeutics, devices and new diagnostic tools. 4) Organisation of a partnering workshop which will bring together patient representatives, scientists, clinicians, industry representatives and capital providers. Its objectives are to find means of facilitating mutual understanding between the parties involved; to identify roadblocks in the development of therapies for rare conditions and to examine possible means around these roadblocks; to support partnerships; to disseminate expert knowledge to all participants, researchers, patient organisations, industry and regulators. The project also addresses the needs of diseases specific research networks.Through bridging the upstream needs for data availability with the downstream issues faced by clinical researchers, the project aims at building synergies with, and acting as a facilitator for other important research and development projects in the fields of rare disorders, genomics and post-genomics, gene and cell therapies. The project addresses the needs of EMEA and industry.The project is of course directly relevant to the activities of the Committee for Orphan Medicinal Products and of the Committee for Medicinal Products for Human Use, including its Scientific Review Group to provide protocol assistance and its safety, efficacy and quality working parties. The project is also expected to have direct benefits for European industry and particularly for small and medium enterprises (SMEs), which account for 80% of OMP applications submitted to EMEA. The platform of services at the centre of the project will provide these industry partners with cost-effective services and solutions that are not yet available. The platform will also steer innovation capacity for new therapies and will reduce the current competitiveness gap of EU industry versus US.
Orphanet, the European database on rare diseases and orphan drugs
Expected results
1) Availability of a European Internet-based information system able to provide the rare disease research community with accurate, reliable and comprehensive European data on existing research projects and networks, registries of cases, directories of patients, cohorts of patients, networks of banks and available biological resources. This information is expected to facilitate exchanges between various stakeholders and to stimulate cooperation between research groups. 2) Availability of an on-line service to speed up the enrolment of patients in clinical research projects. This service is expected to facilitate and to accelerate enrolment of patients in clinical research studies, leading to money savings and to a higher chance to finalise the projects.
The project will benefit paediatric drugs and cancer treatments development.This represents another major public health objective for the EU on which the European Commission envisages specific regulatory and research initiatives. 80% of rare diseases appear at an early age and are directly responsible for 25% of the mortality in childhood. The project is an archetype of the need for action at European level. The specificity of the small number of patients, scarce professional competences and fragmented resources are defining the relevance of this structuring project at EU level.
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Coordinator
Dr Aym, Sgolne INSERM SC11 Hpital Broussais, 102 rue Didot 75014 Paris, France Phone: +33 1 56 53 81 37 Fax: +33 1 56 53 81 38 E-mail: ayme@orpha.net Project web-site: http://www.orphanplatform.org, http://www.orphanxchange.org, http://www.orpha.net. Key words: rare diseases, genetic diseases, orphan drugs, information systems, database, technology transfer, clinical research, clinical trials
Prof. Kriinen, Helena University Turku Department of Medical Genetics Turku, Finland Dr Lassale, Catherine Les Entreprises du Mdicament Paris, France Dr Oosterwijk, Cor Vereniging Samenwerkende Ouder- en Patientenorganisaties Soestdijk,The Netherlands Mr. Poortman,Ysbrand EPPOSI Soestdijk,The Netherlands Ms Jrgen Reden EBE EFPIA Brussels, Belgium Dr Reis Lima, Margarida Instituo de Gentica Mdica Jacinto Magalhes Porto, Portugal Prof. Schmidtke, Joerg Medizinisch Hochschule Hannover Institut fr Humangenetik Hanover, Germany Dr Squiban, Patrick Europabio Strasbourg, France Dr.Voigtlander,Till Medical University of Vienna Institute of Neurology Vienna, Austria
Partners
Dr Buckley, Brendan European Centre for Clinical Trials in Rare Diseases Cork Airport, Ireland Prof. Dallapiccola, Bruno IRCCS Rome, Italy Dr Del Campo, Miguel Universitat Pompeu Fabra Department Cieucies Experimentals Barcelona, Spain Prof. Donnai, Dian The Victoria University of Manchester Academic Unit of Medical Genetics Manchester, United Kingdom Prof. Fryns, Jean-Pierre Katholieke Universiteit Leuven Center of Human Genetics Leuven, Belgium Mrs Greene, Lesley EURORDIS Crewe, United Kingdom Prof. Hennekam, Raoul Universiteit van Amsterdam Dept of Pediatrics and Clinical Genetics Amsterdam,The Netherlands
Acronym: Orphanplatform Project number: LSSM-CT-2004-503246 EC contribution: 400 000 Instrument: Specific Support Action Duration: 24 months Starting date: 01/04/2004
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Anti-Microbial Drug Resistance

EUR-INTAFAR ActinoGEN VIRGIL PNEUMOPEP AMIS PREVIS COBRA micro-MATRIX 68 70 73 75 77 79 82 85
AMDR
EUR-INTAFAR
Inhibition of new targets for fighting antibiotic resistance

Summary
Peptidoglycan biosynthesis and bacterial cell morphogenesis are related phenomena and are totally specific to bacterial cells without even remotely equivalent systems in eukaryotic cells. The enzymes and proteins involved in these processes are thus potential targets for the design of new antibiotics. Interfering with the activities of the participating enzymes or with the protein-protein interactions which take place along these metabolic pathways should result in the perturbation of the bacterial cell cycle and, hopefully, supply new weapons in the fight against dangerous pathogenic organisms such as the methicillin-resistant Staphylococcus aureus (MRSA).
Problem
Although antibiotics have drastically reduced illness and death from infectious diseases, bacteria have exhibited a remarkable capacity to quickly become resistant to one or several classes of antibiotics. For example, in the US, until 2000, Streptococcus pneumoniae infections caused, each year, 100 000 to 135 000 hospitalisations for pneumonia, 6 million cases of otitis media and 60 000 cases of invasive diseases including 3 300 cases of meningitis. Up to 40% of the infections were caused by bacteria resistant to at least one and 15% to three or more antibiotics. The percentage of S. pneumoniae strains resistant to penicillin varies from 3.2 in The Netherlands to 53 in France.Values as high as 60 and 78% are observed in Hong Kong and Saudi Arabia, respectively. Resistance to -lactams is often associated to resistance to macrolides. In 1996, two million cases of nosocomial infections were counted annually in US hospitals. Their global cost ranged from $600 for a urinary infection to $40 000 for a septicemia. Extrapolations made in 1996 in a French study showed that due to nosocomial infections, the stays in hospital were three to seven days longer and the expenses per patient were 750 to 1500 higher. These annual extra costs represented about 2% of the total hospital expenses. Strains isolated from farm animals present even higher levels of resistance. In a recent study performed in Belgium, 95% of the Escherichia. coli strains isolated from poultry, 44% of the strains of bovine origin and 90% strains of porcine origin were resistant to tetracyclines. In all of these cases, resistance to aminoglycosides (streptomycin),chloramphenicol and amoxycillin or ampicillin was also widespread. The increase in antibiotic resistance is thus a global problem, both for nosocomial as well as community-acquired infections.A return to the pre-antibiotic era has even been forecasted. Hence the problem of resistance can only be solved by a multidisciplinary and international approach,which will require a better understanding of the fundamental aspects of bacterial physiology,growth and multiplication mechanisms,
Structure of the Mur D ligase of Escherichia coli (Bertrand et al., J. Mol. Biol., 289, 579-590, 1990) areas which have been relatively neglected in the recent past when compared to eukaryotic systems.
Aim
The aim of this network is to find new potential targets for antibiotics and to use the knowledge accumulated on the antibiotic-resistant forms of some old targets for the design of more efficient molecules. To do so, the fundamental aspects of peptidoglycan biosynthesis and bacterial cell morphogenesis will be investigated. The phenomena which take place at the level of the cytoplasmic membrane and are still very poorly understood will receive special attention.
Expected results
1.The design, synthesis and evaluation of inhibitors or inactivators of the penicillin-resistant DD-transpeptidases. In sensitive bacteria, these enzymes, often referred to as PBPs (for Penicillin Binding Proteins) and which catalyse the final step of peptidoglycan biosynthesis are the targets of penicillins and related compounds. 2.The development of inhibitors of the glycosyltransferase domain of class a PBPs.The reaction catalysed by this enzyme immediately precedes the transpeptidation reaction. No clinically useful inhibitor of this activity is known. 3. Characterisation of the membrane steps involved in the synthesis of the immediate precursor of the transglycosylation reaction (the lipid II) and of the mechanism responsible for the translocation of the disaccharide peptide moiety of lipid II across the membrane and design of inhibitors of these processes.
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4.The development of inhibitors targeting the intracellular steps of soluble precursor synthesis which will rest in part on the differences in the structures of the peptide moieties in several Gram positive pathogens such as Staphylococcus aureus, Streptococcus pneumoniae and Enterococci.Elucidation of the role of the Mur synthetases in Chlamidiae, bacteria which lack detectable peptidoglycan. 5. Understanding the integration of the peptidoglycan manufacturing machineries in the cell morphogenesis and regulation apparatus. A number of proteins which regulate processes such as cell elongation and division are known but their exact modes of action remain to be clarified. Compounds which can interfere with the protein-protein interactions involved in these machineries are potential antibacterial compounds.
Coordinator
Jean-Marie Frre Centre for Protein Engineering, Institut de Chimie B6a, University of Lige 4000 Lige, Belgium Phone: +32 43 663398 Fax: +32 43 663364 Project web-site: (in creation) http://www.ulg.ac.be/cingprot/intafar.htm Key words: antibiotics, peptidoglycan, bacterial cell morphogenesis, transpeptidase, transglycosylase, Lipid II, Mur proteins, Fem proteins
New antibiotics are needed to fight the multi-resistant pathogens. Large pharmaceutical companies have been leaving the field of antibacterial research for a number of years. Although the potential antibiotic market remains huge,up to 90% of infections can be treated with the presently available compounds. The design of specific antibacterial agents directed towards specific species or strains is a sensible strategy from a public health point of view. It is much less interesting commercially. Indeed, a good antibiotic is expected to be taken by the patient over a short period of 1-2 weeks.In consequence, if public authorities do not take charge of the problem, it will remain unsolved at a large cost for society. This project is of prime importance as a springboard to re-activate the utmost important area of antibiotic drugs. A better understanding of the physiology and biochemistry of bacterial cell morphogenesis and peptidoglycan biosynthesis will create new avenues for the design and synthesis of efficient antimicrobials.This will make new opportunities available for companies of different sizes to develop these compounds until they reach the clinical level.
Partners
Molecular Cytology, Swammerdam Institute for Life Sciences, University of Amsterdam,The Netherlands UMR 8619 CNRS, Institut de Biochimie, Universit de Paris-Sud, France Department of Biochemistry of Membranes, Utrecht University,The Netherlands LCM, Institut de Biologie Structurale, Grenoble, France Mikrobielle Genetik, Universitt Tbingen, Germany Department of Microbiology, University of Kaiserslautern, Germany L.R.M.A./E0004, Universit Paris VI, France Division of Microbiology, School of Biochemistry and Molecular Biology, University of Leeds, United Kingdom LCM, Institut de Biologie Structurale, Grenoble, France Centre de Recherches du Cyclotron B30, University of Lige, Belgium Oxford Centre for Molecular Sciences and Dyson Perrins Laboratory, United Kingdom Laboratoire de Chimie et Biochimie, Universit Ren Descartes, France Faculty of Pharmacy, University of Ljubljana, Slovenia Lek, d.d. Pharmaceutical and Chemical Company, Ljubljana, Slovenia ProtNeteomix, Universit de Nantes, France
Acronym: EUR-INTAFAR Project number: LSHM-CT-2004-512138 EC contribution: 11 300 000 Instrument: Integrated Project Duration: 60 months Starting date: 01/01/2005
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AMDR
ActinoGEN
Integrating genomics-based applications to exploit actinomycetes as a resource for new antibiotics

Summary
ActinoGEN is an Integrated Project aimed at developing novel genomics-based approaches to exploit hitherto overlooked genetic resources for new antibiotics.Drug discovery will focus on (1) accessing new antibiotic biosynthetic pathways from diverse actinomycetes that have yet to be cultured; (2) activating cryptic pathways from wellcharacterised actinomycetes;and (3) engineering novel hybrid antibiotics by combinatorial biosynthesis.To greatly accelerate the drug discovery process, a parallel strategy will be to engineer generic hosts optimised to produce high antibiotic yields.With the complete genome sequence of the model actinomycete, Streptomyces coelicolor, and mobilisation of a pan-European effort to apply newly developed multidisciplinary postgenomic technologies, a holistic understanding of the physiology and regulation of antibiotic biosynthesis will be achievable for the first time. This will,in turn,permit rational intervention to engineer generic hosts for high-yield antibiotic production.This synergy of discovery linked to overproduction will place the European biotechnology sector at the forefront of developing much-needed new antibiotics to combat multi drug-resistant pathogens. drugs is no longer considered to be economically worthwhile. Unfortunately, the downturn in drug discovery has coincided with a dramatic worldwide increase in the incidence of resistance to all the antibiotics currently used in medicine.
Aim
The aim of this project is to combine new functional genomic technologies with chemical analysis in an integrated multidisciplinary approach, both to exploit hitherto overlooked genetic resources for new antibiotics and, secondly, develop generic superhosts to produce these new antibiotics in high yields. ActinoGEN proposes three parallel objectives to discover and develop new antibiotics based on exploiting the genetic resources of actinomycetes, hitherto the major source of existing antimicrobials.The first of these is to activate cryptic antibiotic biosynthetic pathways. Recent genome sequencing projects have revealed a genetic potential for actinomycetes to produce many more antibiotics than previously recognised. ActinoGEN will explore how different cryptic pathways can be activated and then determine the structures and activities of the resulting new antimicrobials. The second approach will rely on the discovery of new antibiotic biosynthetic pathways from diverse actinomycetes. The number of actinomycete species that
Problem
Multiple drug-resistant bacteria are a major threat to human health and a significant burden on already stretched medical budgets.This threat is predicted to increase in severity, and remedial actions of reducing antibiotic use in animal husbandry and limiting current prescribing activities for non-lethal human disease are both unlikely to reduce the danger in the short term. Of major concern are antibiotic-resistant nosocomial infections.The economic and societal costs of these hospital-acquired infections are enormous: the UK National Health Service has estimated an annual cost of 1.5 billion for extra patient care and that 5000 deaths result each year. In addition, the incidence of infection by multiple drug-resistant strains of Mycobacterium tuberculosis,the causative agent of the tuberculosis, is rapidly increasing, particularly among the disadvantaged in society. Investment in R&D into antibiotic discovery by the major pharmaceutical companies has declined dramatically in the last 15 years as a perception has taken hold that easily obtained natural products may have been fully exploited.Hence conventional screening of natural products for new
Genetic engineering of cosmid clones for heterologous expression of new antibiotics (provided by Bertolt Gust and Lutz Heide).
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Secreted droplet of antibiotic on the surface of the model actinomycete Streptomyces coelicolor: the shape of the droplet is a consequence of hydrophobicity of the colony surface due to surface-active chaplin proteins (provided by Lubbert Dijkhuizen).
have been isolated to date represents a small fraction of the total in the environment. ActinoGEN will exploit the untapped genetic resource of as yet uncultured species to obtain antibiotic biosynthetic gene clusters that can direct synthesis of new antimicrobials. A third route to new antimicrobials is by combinatorial biosynthesis. Biosynthetic genes from both new and existing pathways will be combined to direct synthesis of new antibiotics with predicted structures. The design of new hybrid molecules will be related to improving antimicrobial activity. A fourth major aim, underpinning the Drug Discovery objectives, is the engineering of generic superhosts for antibiotic production. A ratelimiting step to developing a new antibiotic is yield improvement. Post-genomic analysis permits, for the first time, a concerted and holistic approach to engineering generic superhosts for use in the production of high yields of a wide variety of antibiotics. As part of ActinoGEN, this complementary activity is vital to greatly accelerate the discovery and development of new drugs.
Expected results
1.The establishment of generic procedures for the activation of cryptic antibiotic biosynthetic pathways. 2. Expression of a variety of heterologous cryptic pathways after their transfer to defined superhost antibiotic production strains. 3. Optimised expression of new antimicrobials, and engineered variants thereof, derived from activation of cryptic pathways, together with structural analysis and antimicrobial spectra. 4.The establishment of refined genomic-based procedures for analysis of metagenomes to identify new antibiotic biosynthetic pathways. 5. Expression of a variety of metagenomic pathways after their transfer to defined superhost antibiotic production strains. 6. Optimised expression of new antimicrobials, and engineered variants thereof,derived from metagenomic pathways,together with structural analysis and antimicrobial spectra. 7. Optimised expression of new combinatorial antibiotics, together with structural analysis and antimicrobial spectra.
Genetic and environmental influences on antibiotic production: (A) actinomycetes such as S. coelicolor produce antibiotics late in their development, influenced by growth conditions, (B) a crgA mutant exhibits precocious pigmented antibiotic production, (C) the crgA mutant complemented with a functional copy of crgA introduced on a plasmid vector is delayed in antibiotic biosynthesis, (D) the crgA mutant containing the plasmid vector without the gene, again exhibiting precocious antibiotic production (provided by Ricardo Del Sol and Paul Dyson).
8. Generic antibiotic production superhosts derived by rational genomics-driven manipulation of Streptomyces coelicolor. 9. Refined superhosts strains optimised for production of key new antimicrobials.
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The development of new technologies for antibiotic discovery and production will benefit European SMEs in the biotechnology sector whose remit is to provide new antibiotics.Application of these new genomics-based procedures and technologies for discovery and exploitation of natural products can provide a platform for a renaissance in drug discovery after 15 years of stagnation in this area. The pharmaceutical world market is estimated to amount to 506 billion in 2004. Antibiotics represent one of the principal and indispensable groups of pharmaceuticals. Hence the project can help to stimulate significant growth of European biotechnology SMEs. In addition, new antimicrobials discovered in the course of the project can potentially help alleviate the current crisis in the treatment of multiple drug-resistant pathogens. New antibiotics can provide treatments of last resort for life-threatening diseases such as tuberculosis and nosocomial infections. The efficacy of new antimicrobials will depend on subsequent rigorous testing for toxicity and side effects. However, even in the case of a product with significant side effects, the compound can provide a lead for the subsequent development of safe but effective derivatives, either by chemical modification or by engineering biosynthetic modifications. Thus, there is the potential for these new antibiotics to make a major impact on healthcare in the EU, both at the level of the individual patient and also on healthcare budgets by reducing treatment times in hospitals.
Centre for Microbial Biotechnology,Technical University of Denmark Department of Chemistry, University of Warwick, United Kingdom Department of Microbiology/Biotechnology, Eberhard Karls-Universitt Tbingen, Germany Department of Pharmaceutical Biology, Eberhard KarlsUniversitt Tbingen, Germany School of Biomedical and Molecular Sciences, University of Surrey, United Kingdom Dipartimento di biologia cellulare e dello sviluppo, Universita di Palermo, Italy Groningen Biomolecular Science and Biotechnology Institute, Rijksuniversiteit,The Netherlands Institut de Genetique et Microbiologie, Universit Paris-Sud, France Institut fr Chemie,Technische Universitt Berlin, Germany EntreChem SL, Mieres, Spain Departamento de Biologia Funcional, Universidad de Oviedo, Spain Institute of Biotechnology of Len, Spain
Coordinator
Dr Dyson, Paul School of Biological Sciences University of Wales Swansea, Singleton Park, Swansea SA2 8PP, United Kingdom Phone: +44 1792 295667 Fax: +44 1792 295447 e-mail: p.j.dyson@swansea.ac.uk Project web-site: www.swans.ac.uk/research/ActinoGEN/ Key words: antibiotics, actinomycetes, Streptomyces, antibiotic resistance, genomics
Institut National de la Recherche Agronomique, Laboratoire de Gntique et Microbiologie,Vandoeuvre les Nancy, France Libragen,Villeurbanne, France Institute of Microbiology, Seoul National University, South Korea
Acronym: ActinoGEN Project number: LSHM-CT-2004-005224 EC contribution: 9 395 102 Instrument: Integrated Project Duration: 60 months Starting date: 01/01/2005
Partners
Department of Molecular Microbiology, John Innes Centre, Norwich, United Kingdom Institute of Microbiology,Academy of Sciences of the Czech Republic Department of Chemistry, University of Manchester Institute of Science and Technology, United Kingdom
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VIRGIL
AMDR
European vigilance network for the management of antiviral drug resistance

Summary
VIRGIL is the first European surveillance network capable of addressing current and emerging antiviral drug resistance developments in the field of viral hepatitis and influenza. Focusing first on three major viral diseases, influenza, viral hepatitis B and viral hepatitis C, our strategy will be to build a sustainable, patient-oriented virtual institute on viral drug resistance by integrating the currently fragmented European capacities into interacting subnetworks or virtual departments. Being approachrather than virus-based, one objective of the proposal is to demonstrate a proof of concept that the network structure and the integration process will allow us to easily embrace future drug resistance problems related to other human viruses as well as to new drugs that are currently under development and will come in general use during the life-span of the network. structured into interacting platforms that together will comprehensively cover the problem of virus resistance to antiviral drugs.Being approachrather than pathogen-based,the integration process and the generated tools are flexible enough to embrace future drug resistance problems related to other human virus infections. Until now, antiviral drug resistance has been determined by relying on single specialised laboratories and high standard research groups that are often only capable of addressing one particular aspect.The main objective of the network will be to integrate clinical, technological and research networks and platforms that will interact in a coherent and synergistic manner, as each will provide a broad panel of specific tools for the others.The network will crystallise biomedical research on common objectives targeting viral drug resistance that define specific activities and platforms. VIRGIL is structured into seven integrated platforms centred around the patients, each focusing on a topic contributing towards the project objectives.
Expected results
The creation of a European Network of Excellence on the antiviral drug resistance topic represents an opportunity to achieve real cooperation among leading scientists in the field.This should significantly improve our knowledge on drug resistance. VIRGIL will fill the following gaps: VIRGIL will integrate into a coherent network leading institutions expertise within Europe for antiviral susceptibility followup and testing. VIRGIL will set up centralised databases to provide a unique opportunity to track and model the emergence of resistance and its consequences for population transmission. VIRGIL will create a unique EU antiviral resistance sample archive of serum and tissue samples and virus strains, which can be used to test (anti)viral fitness/provide reference material for testing new drugs on emerging ADR viral strains. VIRGIL-IMPACT will provide information about costs, morbidity, viral evolution, drug use, geography and other public health interventions, and can provide a model system for other disease networks where antimicrobial resistance is an emerging problem. VIRGIL-MODELS will establish a platform that is capable of analysing antiviral drug resistance in all its facets through the implementation of in vitro systems (test tube or enzyme assays), cell culture systems, and in vivo animal models. VIRGIL-DRUGPHARM will allow the formulation of novel testable hypotheses when dissecting which factors contribute to drug resistance in specific cohorts. In particular, pharmacokinetic parameters such as the dose and the treatment schedule of a particular drug will be analysed.
Problem
Acute and chronic viral infections represent a major public health problem in Europe and worldwide, responsible for a major socioeconomical burden.The development of new antiviral drugs and new diagnostic tools in the past decade has played a major role in the improvement of patient care, treatment of viral diseases and has extended the quality and duration of human life. However, their increased use and misuse in medicine has given rise to viral drug resistance leading to treatment failure and enhanced costs for health care and society. Furthermore, there is no global programme at European scale to develop strategies for the surveillance and containment of viral resistance to antiviral agents.Therefore, there is a clear need to implement a European programme to optimise patient care and to minimise the emergence and spread of antiviral drug resistance.
Aim
The overall objective of the VIRGIL Network of Excellence is to set up the first-ever EuropeanVigilance Network capable of addressing current and emerging antiviral drug resistance developments that will allow for the management of this critical problem in Europe. Coordinated by INSERM (the French Institute for Health and Medical Research), the networks activities started in May 2004 with the initial task of integrating the fragmented European capacities and major expertise in the field into a single coherent Network of Excellence.VIRGIL initially gathers 55 organisations, including more than 60 academic laboratories and seven companies from 12 European countries.Focusing initially on three major diseases (viral hepatitis B, viral hepatitis C and influenza), its mission is to build a sustainable, patient-oriented virtual institute
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Microchip technology has already had a significant scientific impact in cell biology but much less so in infection including virology. Therefore a successful outcome with early detection of drugresistant mutations in influenza to anti NA and M2 drugs, or in viral hepatitis B and C to new specific inhibitors would have a major impact in a wide sense. Importantly the method could be applied to other viruses not at present in the network such as poxviruses,since it is expected that smallpox will rapidly become a target for new antiviral molecules. It should also be possible to design chips to detect entirely novel NA and HA molecules and in this manner the network could also contribute to influenza pandemic planning.
Coordinator
Zoulim, Fabien INSERM Unit 271 and liver department Institut Universitaire de France 151 Cours Albert Thomas 69003 Lyon, France Phone: + 33 4 72 68 19 70 Fax: + 33 4 72 68 19 71
VIRGIL activities should result in an improved and standardised monitoring of drug resistance, with the development of new rapid diagnostic tools and susceptibility testing. One achievement of the VIRGIL network will be to establish correlations between the different clinical, genotypic and phenotypic analyses performed in expert European laboratories to define new and internationally recognised standards for viral drug resistance testing. As an extension, the network will ensure the spread of knowledge and technological innovation in sites where a critical need for these technologies has been identified, i.e. eastern and southern Europe. It will also foster education and knowledge of health care providers and physicians regarding the optimal monitoring of drug resistance and up-to-date strategies that reduce the risk of selection of resistant viral strains. Guidelines for clinical practice to monitor drug resistance but also for a rational use of antivirals will be generated and assessed. They will take into account the diversity of social, political and economic settings within Europe. Education programmes targeting patients and the general population will be organised to encourage compliance to medical monitoring and therapy through understanding of science. Another objective of the VIRGIL network will be to constantly evaluate new strategies to combat viral drug resistance.Therefore, it will translate the results into new clinical trials for the optimal use of drug resistance assays as well as for the evaluation of novel treatment strategies to prevent or overcome development of viral resistance. To implement these strategies, partnerships with diagnostic and pharmaceutical industrial partners within and beyond the actual network will be launched. Furthermore, all these actions should allow us to establish a stable and long-lasting NoE at the European level with the capacity to rapidly and reliably determine resistance to new drugs and to determine drug susceptibility of emerging viral strains under the selective pressure of new treatments.This capacity to adapt and react to new clinical situations based on the expertise of the teams and on the possibility of including new partners during the duration of the project will be a major characteristic of this network.This germ centre will allow expansion and modification to create a network that can cover virtually any viral infection for which antiviral drug resistance is clinically relevant.
E-mail: zoulim@lyon.inserm.fr Project web-site: www.virgil-net.org Key words: antiviral, drug, resistance, hepatitis, influenza, flu, HCV, HBV, virus
Partners
11 France 12 Germany 8 United Kingdom 2 Belgium 3 The Netherlands 6 Italy 4 Spain 1 Greece 2 Switzerland 1 Poland 3 Sweden 1 Austria 1 Israel
Acronym: VIRGIL Project number: LSHM-CT-2004-503359 EC contribution: 9 000 000 Instrument: Network of Excellence Duration: 48 months Starting date: 01/05/2004
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PNEUMOPEP
AMDR
New methods of treatment of antibiotic-resistant pneumococcal disease

Summary
The innovations of this project are the new targets, identification of completely new lead compounds,a new approach to adjunctive therapy and a new method of delivery of the compounds. Streptococcus pneumoniae imposes a huge disease burden on humans:it is the primary cause of pneumonia and it is the second most common cause of meningitis. There is a pandemic of multi-drug resistant pneumococci and treatment is compromised. Even if antibiotics kill the bacterium, they can fail to prevent death or neurological damage after meningitis, due to the acute toxaemia.The first event in toxaemia is release of proinflammatory or toxic pneumococcal products, probably exacerbated by antibiotics. The pneumococcal toxin pneumolysin fulfils both definitions: it is directly toxic to mammalian cells and it stimulates release of inflammatory mediators from host cells.For this reason,and because the toxin is essential for the survival of the bacterium in vivo,pneumolysin will be a target of this project.A second target will be the cell surface proteinases involved in adhesion and invasion, which are important virulence factors for the pneumococcus.These proteins represent new targets and their validation as targets has been done.The new treatment will be based on binding peptides isolated from a series of large phage display libraries or based on small molecules identified by high throughput screening. Following screening of the phage libraries the most promising peptides will be evaluated on the basis of binding affinity and neutralising action in vitro.The peptides and small molecules will be formulated in chitosan for nasal delivery. Model of pneumolysin monomer
Aim
To identify lead compounds for the treatment of pneumococcal disease by inhibition of the pneumococcal toxin, pneumolysin. To identify lead compounds for the treatment of pneumococcal disease by inhibition of the pneumococcal zinc metalloproteases. To identify new methods for the delivery of the new anti-pneumococcal compounds.
Expected results
Isolation and identification of peptides and/or small molecules as lead compounds for the treatment of pneumococcal disease. Use of the lead compounds,formulated in chitosan,for nasal delivery of anti-pneumococcal drugs.
Problem
This project is being undertaken in response to the need to find new methods of treatment of disease due to Streptococcus pneumoniae.This bacterium is a major cause of community-acquired pneumonia, meningitis, bacteraemia and otitis media and it exhibits high rates of multi drug-resistance in countries worldwide. More than ever before, modern drug discovery is dependent on highthroughput screening.Therefore,the drug discovery process is shifting focus from identifying suitable candidate drugs which remains an essential but time-consuming goal to identifying suitable lead compounds in order to maximise the cost-effectiveness and speed of the subsequent lead optimisation process. Peptide sequences specifically binding to pneumolysin or to metalloproteinases (indicated as "Target" molecules in the picture) will be identified through affinity selection on solid phase (microplates or magnetic beads) of several different phage displayed random peptide libraries, having different length and level of constrain. Phage clones bearing specific peptide ligands will be isolated and the sequence of the displayed peptide will be determined by sequencing of the corresponding single-strand DNA. Characterization of biological properties of the selected peptides will be performed.
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AMDR
The results from the project will lead to new treatments of pneumococcal pneumonia, meningitis and bacteraemia and new formulations for delivery of treatment. Pneumococcal disease makes significant demands on health care systems but the rapidly increasing rate of antibiotic resistance in pneumococcal strains is impacting on clinical management of pneumococcal disease. At one level the project will confront this issue by producing new antimicrobial agents directed at hitherto unexploited targets. The project aims, however, to develop these new antimicrobial molecules targeted at a single, highly important bacterial species rather than taking the traditional approach of narrow- and broad-range antimicrobial drugs. The use of targeted drugs is predicted to reduce the intensity of selection for any particular resistance mechanism since no selective pressure is applied to species other than the target organisms, thus reducing the pool of organisms contributing to the spread of any resistance mechanism. Reduction in the frequency of resistance will significantly prolong the shelf life of any antimicrobial drug. The treatments developed from this project will also address the toxaemia in pneumococcal disease that is not addressed by conventional antibiotics. The project will evaluate if a new drug delivery system based on chitosan will enhance the effectiveness of anti-infective compounds.
Coordinator
Prof.Andrew, Peter W Department of Infection, Immunity & Inflammation University of Leicester University Road Leicester, LE1 9HN, United Kingdom Phone: +44 116 2522951 Fax: +44 116 2525030 Email: pwa@le.ac.uk Project web-site: www.le.ac.uk/iii/eu/pneumopep Key words: antibiotic resistance, Streptococcus, pneumonia, meningitis, pneumolysin, metalloproteinase
Partners
Dr Oggioni, M R Dipartimento di Biologia Molecolare Universit degli Studi di Siena Policlinico Le Scotte (lotto 5; piano 1) Siena, Italy Prof.Teti, G Dipartimento di Patologia e Microbiologia Sperimentale, Universit di Messina Messina, Italy Dr Gill, I J Bioanalytical Department West Pharmaceutical Services Drug Delivery & Clinical Research Centre Ltd Nottingham, United Kingdom Mr Jarosz,T Essais Cliniques-Evaluation-Epidmiologie-Statistiques Paris, France
Acronym: PNEUMOPEP Project number: LSHM-CT-2005-512099 EC contribution: 1 500 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/06/2005
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AMIS
AMDR
Antimicrobials by immune stimulation

Summary
AMIS aims to use the strength of our own innate immune system to design antimicrobial drugs for future generations.Antimicrobial proteins in our immune system are often combined with inflammatory signals in one single molecule.AMIS will take that same approach and reshuffle different parts of different molecules to make novel effector molecules that still have these combined functions but are optimally adapted for therapeutic intervention. Within our innate immune system many molecules have been identified over the last years that are involved in direct or indirect clearance of bacteria.The consortium will select the most promising and innovative compounds with this dual mode of action and: design proteins with anti-microbial activity in combination with an inflammatory trigger, targeting extra cellular bacteria design proteins with inflammatory priming capacity (without extra anti-microbial activity); targeting intracellular bacteria discover new modulators to dampen inflammation.
Problem
The tremendous success with which antibiotics have been used to combat infectious diseases is under serious threat from the increasing development of antimicrobial resistance. Without new treatment approaches to address antimicrobial resistance, this threat will continue to rise.To fight infectious diseases effectively in the future we have to broaden the approaches in therapeutic intervention.There are three ways by which the therapeutic intervention of infectious diseases can be broadened. The first is to design drugs that have a smaller chance for resistance development (targeting evolutionary conserved structures is one key element here).The second is to design drugs that are as different in mechanism of action as we can envision. The third is to combine drugs. AMIS (Antimicrobials by Immune Stimulation) combines these three strategies in a highly innovative approach.
Aim
Activators, receptors, effectors and inhibitors are an integral part of the complex mechanism of interaction in the innate immune system, combining cellular stimulation and anti-microbial action. These interaction mechanisms form the core focus of the research project envisaged by the consortium. The underlying theory is that the multitude of triggers needed to get a full-blown immune response is an intrinsic prerequisite to keep the process localised.That is why we will aim at subtle immunostimulation or priming,which will,in bacterial infections, be accompanied by an extra trigger, locally provided by the bacterial products at the site of infection. In its pursuit of a novel approach to address antimicrobial resistance, the consortium has formulated three main research objectives.
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AMDR
Expected results
Make an array of fusion proteins that combine strong antimicrobial with inflammatory signals so that these two actions work in concert. By combining the best that we can find in our innate immune system we can tune the new molecules to perform better in certain specific infections than Nature has provided so far.Furthermore we aim to learn from our innate immune system how to effectively recognise and kill a bacterium for millions of years without developing major resistance.
Partners
Prof. Krnke, Martin Institute for Midical Microbiology, Immunology and Hygiene Medical Centre University of Cologne Cologne, Germany Prof. Espervik,Terje Department of Cancer Research and Molecular medicine Norwegian University of Science and Technology Trondheim, Norway Prof. Peschel, Andreas Faculty of Medical Microbiology, Cellular and Mollecular Microbiology Group University Hospital Tbingen Tbingen, Germany Prof. Bjrck, Lars Department of Cellular and Molecular Microbiology Lund University Lund, Sweden Dr Haagsman, Henk P . Department Public Health and Food Safety Faculty of Veterinary Medicine Utrecht University Utrecht,The Netherlands Dr. Peter Antal-Szalmas Department of Clinical Biochemistry and Molecular Pathology
The collaborative research in AMIS will lead to proof-of-principle for a novel treatment approach to address antimicrobial resistance by combining the innate immuno-stimulation with the antimicrobial capacity of naturally occurring substances of the human innate immune system. Parts of that system have been proposed and tried before with antimicrobial peptides from insects and other species and activation of the immune system by bacterial compound [Toll Like Receptor (TLR) ligands or small molecules that affect the signalling pathway of TLRs] as examples. However toxicity in the first example and over-activation of the immune system combined with redundancy in the second example are inherent drawbacks in these alternative approaches.
The consortium
Medical and Health Science Centre Debrecen, Hungary Dr. Herman Groen
Coordinator
Dr van Strijp, Jos Eijkman Winkler Institute University Medical Centre Utrecht Heidelberglaan 100 3584 CX Utrecht,The Netherlands Phone: +31 30 250 6528 Fax: +31 30 254 1770 E-mail: j.vanstrijp@azu.nl Key words: immunology, infections, novel antimicrobial approach, immune stimulation, fusion compounds
IQ Corporation Groningen,The Netherlands Dr. Shai Yarkoni Target-In Ltd. Kfar-Saba, Israel
Acronym: AMIS Project number: LSHM-CT-2004-512093 EC contribution: 2 100 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/01/2005
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PREVIS
AMDR
Pneumococcal resistance epidemicity and virulence an international study

Summary
Human pathogens emerging in the contemporary environment face two main kinds of evolutionary challenges: A. survival and growth in the antibiotic-rich milieu makes it essential that the bacteria acquire genetic traits of resistance B. successful drug-resistant strains must also be able to compete with other members of the species for colonisation, geographic spread and disease in the human host. The main purpose of the programme PREVIS is to examine the interplay of these two challenges and also obtain insights on how host factors and ecological/societal factors (antibiotic use, day-care centre attendance etc.) modulate the epidemiology of drug-resistant and drugsensitive pneumococcal disease in diverse settings in northern,southern and eastern Europe.PREVIS will provide an integrating platform to study important and unexplored aspects of microbial and host factors related to pneumococcal disease/pathogenesis,epidemiology/transmission,and molecular mechanisms for resistance development. A broadening of knowledge on these issues should lead to improved and focused treatment, prevention and intervention strategies towards these common community-acquired infections. from this major ecological reservoir are widely spread in Europe and in other parts of the world, threatening effective antibiotic therapy. For decades penicillin has been the drug of choice for treating pneumococcal infections, but increasing levels of penicillin resistance, up to 50% in some areas, has resulted in the use of alternative antibiotics. However, this has led to the development of resistance to many alternative antibiotics as well, and vancomycin is the last drug of choice, especially when treating invasive pneumococcal infections caused by DRPn clones, since vancomycin resistance has not been observed. Of major concern is the emergence and wide distribution of multiresistant isolates (those resistant to more than two different classes of antibiotics) globally, creating further treatment problems. The PREVIS programme aims to address several major questions, such as: Why do pneumococci sometimes act as devastating pathogens causing a severe disease with sometimes a fatal outcome, while in other instances cause a non-invasive upper respiratory tract infection, or even just reside harmlessly in the nasopharynx without symptoms of disease? Are those pneumococci found among healthy children of the same genetic lineages as those pneumococci causing invasive disease? Are there differences in the severity and nature of diseases caused by DRPn and drug susceptible (DSPn)? How are transmissibility and virulence affected by antibiotic resistance determinants?
Problem
Streptococcus pneumoniae remains among the most important causes of life-threatening community-acquired diseases such as pneumonia, septicaemia and meningitis, particularly in high-risk groups such as young children, HIV-infected individuals and the elderly. The introduction of penicillin and other antimicrobial drugs caused a dramatic reduction in mortality of all pneumococcal diseases except meningitis. However, pneumococcal disease attack rates have not decreased and the annual global mortality rate of pneumococcal disease is still estimated to be over one million deaths per year. In the United States, pneumococcal infections remained a major cause of potentially life-threatening diseases with fatality rates in a similar range as those of AIDS,prostate and breast cancer.Streptococcus pneumoniae is also a major cause of upper respiratory tract infections such as otitis media and sinusitis.While these afflictions are seldom life-threatening they are major contributors to health care costs and antibiotic use. Not only is the human host the virtually exclusive target of pathogenic pneumococci but the nasopharynx is also the main ecological reservoir of this bacterial species. Up to 60% of healthy children attending day-care centres were found to be colonized by S. pneumoniae. Drug-resistant pneumococcal clones (DRPn) emerging
Streptococcus pneumoniae
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AMDR
Aim
The main objective of PREVIS is to examine the interplay between how pneumococci acquire genetic traits of resistance and how successful resistant and susceptible strains may cause colonisation, transmission and disease,involving both bacterial virulence properties as well as host factors.
6. identify novel approaches to the development of antivirulence drugs 7. identify the genetic/biochemical mechanisms of the fitness cost of penicillin resistance and compensatory mechanisms that must exist in epidemic clones of DRPn 8. identify the role of viral illness and immunological/genetic factors in the susceptibility of children to invasive pneumococcal disease 9. estimate the threshold levels of antibiotic consumption in the community that select for resistance 10. develop a web-based data management infrastructure coupled with advanced machine learning tools for automated data-mining of predictive associations.
Expected results
1. determine the frequency and clonal types of DRPn and DSPn causing invasive disease and colonising healthy carriers 2. clone- and serotype-specific estimates of disease potential for invasive pneumococcal disease 3. using a microarray developed in PREVIS, from the two genome sequences of TIGR4 and R6 and comparative genomics, we aim at identify factors involved in pneumococcal pathogenesis 4. whole-genome sequencing of a Streptococcus mitis strain, which is a frequent source of heterologous genes and gene fragments which may become building blocks of resistance determinants in S. pneumoniae 5. show whether antibiotic resistance determinants affect pathogenhost interactions and identify host factors important for susceptibility to invasive pneumococcal disease
Pneumococcal disease caused by both DRPn and DSPn results in a substantial portion of the estimated health care costs of infectious diseases in Europe. Globally, mortality from pneumococcal diseases has remained among the highest of all infectious diseases. Yet this potentially dangerous human pathogen also uses the healthy human carrier as its global ecological reservoir. By gaining better knowledge about the spread of DRPn and DSPn, microbial and host factors important for pneumococcal pathogenesis, mechanisms for the development of antibiotic resistance and the role of environmental factors such as antibiotic consumption for the emergence and spread of antibiotic resistant pneumococci, we will create a platform for improved treatment and more focused prevention and intervention strategies.Also, as the prevalence of multi-resistant strains continues to increase, creating further treatment problems, novel concepts for making drugs are of major importance. In this project we intend to develop lead substances for novel so-called anti-virulence drugs.If this approach turns out to be successful we will have a new drug for treating pneumococcal infections irrespective of whether or not the bacteria are resistant to antibiotics.
Drug resistance
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AMDR
Coordinator
Dr Henriques Normark, Birgitta Department of Bacteriology Swedish Institute for Infectious Disease Control Nobels vg 18 171 82 Solna, Sweden Phone: +46 84752413 Fax: +46 8302566 E-mail: Birgitta.Henriques@smi.ki.se Project web-site: www.previs.net Key words: Streptococcus pneumoniae, antibiotic resistance, molecular epidemiology, pathogenicity, innate immunity
Prof. Normark, Staffan Microbiology and Tumorbiology Center Stockholm, Sweden Prof. Hakenbeck, Regine University of Kaiserslautern Kaiserslautern, Germany Prof.Wolf-Watz, Hans INNATE pharmaceuticals Ume, Sweden Dr Gudnason,Thorolfur Directorate of Health-Infectious Disease Control. Seltjarnanes, Iceland Prof.Almeida, Jonas S Instituto de Biologia Experimental e Tecnolgica, IBET Oeiras, Portugal Dr Urbaskova, Pavla National Institute of Public Health Prague, Czech Republic
Partners
Dr Ekdahl, Karl Dept of Epidemiology Swedish Institute for Infectious Diseases, SMI Solna, Sweden Prof. de Lencastre, Hermnia Instituto de Tecnologia Qumca e Biolgica (ITQB) Oeiras, Portugal Prof. Spratt, Brian Imperial College London Department of Infectious Disease Epidemiology London, United Kingdom Prof. Kristinsson, Karl G Landspitali University Hospital Reykjavik, Iceland Dr Jonsdottir, Ingileif Landspitali University Hospital, Department of Immunology Reykjavik, Iceland Prof. Melo-Cristino, J Laboratory of Microbiology Faculdade de Medicina de Lisboa (FML), Lisbon, Portugal
Acronym: PREVIS Project number: LSHM-CT-2003-503413 EC contribution: 3 000 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/01/2004
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AMDR
COBRA
Combating resistance to antibiotics by broadening the knowledge on molecular mechanisms behind resistance to inhibitors of cell wall synthesis
Summary
We aim at the elucidation of the molecular mechanisms of resistance to inhibitors of cell wall synthesis in bacteria responsible for severe nosocomial and community-acquired infections. Our STREP is focused on -lactams, the major class of antibiotics in current clinical use, and on resistance due to modifications of the cell wall synthesising machinery and to production of -lactamases, the most prevalent mechanisms in Gram-positive and Gram-negative bacteria,respectively. These studies will form a reference to globally assess the modifications of the structure, function, and dynamics of the peptidoglycan assembly pathways responsible for emergence of resistance including the 3-D structure of relevant components and possible targets. It will identify new -lactamases,determine their 3-D structure and elucidate different aspects of the regulation of their gene expression and the mechanisms responsible for their mobility. A) Penicillin-binding proteins (PBPs) and critical associated factors. The peptidoglycan is a complex structure, the synthesis of which involves multiple coordinated steps within and outside of the cytoplasm. The complete disaccharide-peptide unit linked to the lipid carrier, once translocated through the cytoplasmic membrane, is polymerised by protein complexes involved in cell elongation (elongase) and division (divisome). These complexes include the PBPs (penicillin binding proteins) of classes A and B that belong to the superfamily of the penicilloyl serine transferases and are the targets of the penicillins. According to the modules they contain, they display D,D-transpeptidase, D,D-carboxypeptidase and glycosyltransferase activities. Production of D,Dtranspeptidases that are inefficiently inactivated by the drugs, commonly referred to as low-affinity PBPs, is the main mechanism responsible for clinically relevant -lactam resistance in streptococci, staphylococci, and enterococci. Due to the complexity of the peptidoglycan assembly pathway, analyses of the mechanisms of resistance has been mainly limited to easily detectable modifications of the drug targets, such as the level of production of the PBPs and their interaction with -lactams. However,recent analyses support the view that genes non-essential for viability are required for expression of resistance mediated by low-affinity PBPs and other factors.Among these are: (i) biosynthetic enzymes adding the side chain to the pentapeptide stem; (ii) regulatory factors, that control as yet unknown responses of the bacteria to the drugs; and (iii) transglycosylases which appear to co-operate in an undefined manner with the D,D-transpeptidase acitvity of low-affinity class B PBPs for peptidoglycan polymerisation in the presence of lactams. In rare cases, mutations in these chromosomal genes have been detected in resistant bacteria but the extent of such modifications and the role of the encoded protein are largely unknown. Analysis of the role of other components of the divisome and the elongase complexes have not been developed since the metabolism of the lipidlinked peptidoglycan precursors and their delivery to the polymerisation complexes is poorly understood. B) -lactamases. Among clinical Gram-negative isolates, the major mechanism of resistance to -lactam antibiotics is related to the production of hydrolytic enzymes:the -lactamases.To counter this problem, the pharmaceutical industry has marketed novel classes of -lactams. However, the use of these new drugs was quickly followed by the emergence of new -lactamases including those with
Problem
Antibiotics are not like other drugs in that they act against bacteria and not the human host.Therefore the evolution of resistance under the selective pressure of antibiotics after exposure of populations (human, animal) raises major therapeutical issues. This programme addresses the general problem of resistance to antibiotics and concerns the understanding of the mechanisms of resistance, in particular to inhibitors of cell wall synthesis.Among these are the lactams, one of the most important classes of antibiotics, if not the most broadly used antibiotics worldwide. The rates of -lactam resistance for many common species found in infections have reached high levels in the community, as well as in the hospital.While in Grampositive organisms this resistance is mainly due to altered targets, in Gram-negative organisms, acquired resistance to -lactams is essentially due to the presence of plasmid-encoded -lactamases or the over-expression of chromosome-encoded -lactamases.This latter resistance can be enhanced by associated impermeability or efflux mechanisms. Since many pathogens are multiresistant, there will be an eventual limitation in the choice of antibiotics useful for primary treatment and therefore a promotion of a vicious circle facilitating the emergence of new resistances.
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AMDR
expanded-spectrum activity many of which evolved from previous existing -lactamases.This process involved the three classes of lactamases (classes A, C, and D) belonging to the superfamily of penicilloyl serine transferases, that also includes the PBPs, and the class B enzymes regrouping the metallo--lactamases (Zn++dependent).While new enzymes are discovered almost every day and have to be explored, the reason for the spreading of several novel enzymes world-wide remains unknown and the factors modulating their expression as well as the vehicles for mobility and spreading of these genes have to be thoroughly studied.
Gram-negative organisms. For several of these enzymes, gene expression and the molecular basis of their dissemination will be studied.The catalytic properties, the structure-activity relationships and the 3D structure of some of them will be determined with regard to their activities against the antibiotics.The contribution of additional factors, such as outer membrane permeability and efflux pumps, to high-level resistance to -lactams will be investigated in detail.
Expected results
Understanding the role of those amino acid residues in PBPs that are essential for the expression of resistance and their contribution to the structure of the PBP D,D-transpeptidase domains. Understanding the biochemical role of the associated critical factors in the pathway of peptidoglycan synthesis, their structure, and their role in non -lactamase-mediated resistance; with respect to various regulators, and understanding the mechanisms by which they interfere with the expression of resistance. Understanding the diversity of the structures of the -lactamases observed and studied, and understanding the role of the amino acid residues essential for their catalytic properties. Understanding the genetic environment of the -lactamase genes and its contribution to expression of resistance, gene dissemination as well as the associated role of porins and efflux systems in the expression of resistance.
Aim
This project focuses on the understanding of molecular mechanisms of resistance to -lactams and other cell wall inhibitors in clinical Gram-positive and Gram-negative pathogens. We aim at studying different enzymatic properties and structural features of class B PBPs involved in -lactam resistance, as well as different auxiliary proteins, among which the class A PBPs and other enzymes involved in the synthesis of substrate structures used by these class A and B PBPs. We also intend to find, in the cytoplasmic and in membrane steps of the peptidoglycan synthesis,other critical factors,including regulators, interfering with the expression of resistance to cell wall inhibitors and possible new resistance-conferring targets. The study of lactamases will include an extensive search for, and characterisation of, novel extended-spectrum -lactamases and carbapenemases in
3 D model of the chromosomal L2 -lactamase of Stenotrophomonas maltophilia involved in -lactam resistance of a pathogen found in cystic fibrosis and nosocomial infections.
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AMDR
This programme addresses the general problem of resistance against a class of antibiotics widely used in the community and in hospitals. Any progress, even the smaller ones, in the understanding of these mechanisms will be of benefit to academia, public health and industry. It will increase our knowledge of insufficiently explored and new mechanisms of resistance toward cell wall inhibitors. It will lead to the deciphering and the discovery of novel mechanisms including the role of several auxiliary proteins involved in resistance.The isolation of -lactamases, PBPs and other components essential for the expression of resistance to -lactams and other cell wall inhibitors, reinforced by knowledge of their 3-D structure, will allow for the future setup of assays to screen for new inhibitors and will improve drug design.The knowledge of the sequence of different targets will be used to create databases containing new -lactamases and new PBP alterations linked to resistance. Particular mutations responsible for resistance could then be used to develop sequence-based molecular diagnostic tools. Discovery of novel mechanisms of resistance will result in the identification of new phenotypes helpful for the detection of resistance in clinical laboratories.This will aid in the interpretation of susceptibility and resistance to different classes of cell wall inhibitors, in particular -lactams. Finally,transmission and acquisition of resistance by new strains is one of the major factors in resistance dissemination.A better knowledge of these mechanisms should facilitate the recognition of the antibiotics most powerful in selecting for the mechanisms studied.Understanding of the transmission mechanisms is a crucial step in preventing resistance as well as in guiding optimal antibiotic usage. Key words: resistance to antibiotics, cell wall synthesising machinery, PBP, non-PBP factors and resistance, -lactamases, catalytic mechanisms, structural studies, gene acquisition and mobility, Gram-positive and Gram-negative organisms.
Partners
Centre dIngnierie des Protines, Lige, Belgium Department of Sciences, Swammerdam Institute for Life Sciences, Molecular Cytology,Amsterdam,The Netherlands Microbiology, University of Kaiserslautern, Germany Medical Microbiology, Zrich, Switzerland Regulation of gene expression/Centro de biologia molecular severo ochoa, Campus universidad autonoma, Madrid, Spain Biochemistry/Universit Paris XI / IBBMC, Orsay, France Department of Chemistry, University of Warwick, United Kingdom IBS, Institut de Biologie Structurale, Grenoble, France Bacteriology, University Paris XI, Le Kremlin Bictre, France Servicio de Microbiologia, Hospital Universitario Ramon y Cajal, Madrid, Spain Antibiotic Resistance Monitoring & Reference Laboratory, London, United Kingdom
Coordinator
Prof. Gutmann, Laurent Microbiologie INSERM EMI0004 Universit Paris VI, Laboratoire de Recherche Molculaire sur les Antibiotiques 15 rue de lcole de Mdecine 75270 Paris CEDEX 06, France Phone: +33 1 42 34 68 62 Fax: +33 1 423 25 68 12 E-mail: laurent.gutmann@hop.egp.ap-hop-paris.fr; gutmann@ccr.jussieu.fr Project web-site: http://www.antibior.com
Molecular Microbiology, National Institute of Public Health,Warsaw, Poland Department of Pathology and Microbiology, University of Bristol, United Kingdom Dipartimento di Biologia Molecolare, Sezione di Microbiologia, Siena, Italy Inserm Transfert SA, Paris, France
Acronym: COBRA Project number: LSHM-CT-2003-503335 EC contribution: 2 980 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/02/2004
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micro-MATRIX
AMDR
Workshop on strategies to address antimicrobial resistance through the exploitation of microbial genomics
Summary
Recent genomic technologies allow the study of global physiological processes in microbes.Their application to the study of pathogens allows improved searches for new medicines to combat infection and to better avoid the emergence of resistance against them. It will also help to anticipate therapies for new emerging diseases and to devise treatments to help individual patients to overcome each infection. Predictive microbiology,based on genomic analysis,may also be used to anticipate the presence of unexpected potential pathogens. Both industrial and sustained public sector efforts are needed to fully develop the promising potential of this research frontier of the microbial world.
Expected results
The workshop conclusions will be centred on proposing to the European Commission a realistic roadmap to implement a research activity based on functional genomics to tackle the problem of antibiotic resistance and discovery with sufficient industrial, clinical and academic participation to guarantee its long term success.
How genomics can help to combat antibiotic resistance? Genomics has been applied to identify new inhibitable bacterial targets, but it can be used as well to gain valuable knowledge on how bacteria behave during infection, how they respond when their proliferation is challenged or when they are treated with an antibiotic. Target identification Comparative genomics yields information on the universality of targets in important pathogens. Moreover, it identifies those genes that being absent in humans and animals are less likely to produce problems when their function is blocked. A recent genomic search comparing the genomes of three important pathogens, Haemophilus influenzae,Streptococcus pneumoniae and Staphylococcus aureus indicates that more than 350 bacterial genes are possible targets (Payne, D. J. Microbiology Today, 2004, 31: 55-57). After finding that a gene may be a target, further work is required to obtain information on what specific property or domain of the encoded protein is the one that can be successfully inhibited. A substantial amount of additional research may still be needed before an assay for HTS (high throughput screening) can be devised and validated. The future of genomics in target identification Genomics can help to refine and validate targets by analysing changes in the expression of genes that take place in the microbes when they are subject to stressful conditions that mimic the environment confronted during the process of infection. Progress in molecular modelling and in the synthetic skills needed for mimicking protein surfaces are still required to fully exploit the knowledge derived from the study of the interactome. In the future the study of the interactome will identify the precise domains in some target molecules that are required for the function of proteins that establish interactions required for the survival of the pathogen and for its interaction with the host. If suitable mimics are synthesised they can be used as scaffolds to build an altogether new class of bacterial inhibitors.
Problem
The discovery of new antibacterial agents against resistant microorganisms is an urgent and vital need. All EU member states unanimously agreed that antimicrobial resistance was no longer just a national problem, but a major international issue requiring a common strategy at European level (The Copenhagen Recommendations Report from the European Union Conference on The Microbial Threat, September 1998, 1). Recommendations released following this meeting expressed four important issues, among them the need to carry out research to fight the problem of antimicrobial resistance. The social costs incurred by the incidence of infectious diseases in the population at large,and in particular the elderly and the productive age sectors,are enormous.Hospitalisation costs per patient run above about 500 per day. Curbing the spread of resistant pathogens will result in the attainment of high standards in human health care,a main component of the quality of life, as a clear priority for the European Union. It will reduce social and public healthcare costs and will therefore have a beneficial impact on the citizens of the EU. Specifically it is anticipated that the ability to effectively treat microbial infections will reduce morbidity, and have a positive impact on health management policies of the EU member states.
Aim
To discuss microbial functional genomics as a powerful and innovative tool to discover new cellular targets that will be used to counteract bacterial resistance to antibiotics and to further avoid the generation and spread of new resistances.
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AMDR
How to avoid the path to resistance Pathogens become resistant to antibiotics by synthesising new proteins or modifying part of their physiology. In most cases the acquisition of resistance makes resistant bacteria less efficient to compete against their non-resistant relatives in the absence of the antibiotic.This extra burden can in turn be minimised by the acquisition of compensatory mutations that counterbalance the decrease in fitness. Compensatory mutations are difficult to revert and contribute in some cases to maintain a proportion of resistant individuals within pathogen populations (Andersson, 2003, Persistence of antibiotic resistant bacteria, Current Opinion in Microbiology 6: 452-456). Resistance is both inheritable and transmissible. Blocking the horizontal transfer of resistance,although of limited therapeutic value, is a possible way to prevent the spread of antibiotic resistance to the susceptible pathogen populations. Functional genomics supplies data on how bacteria respond to different environments by adjusting the rates at which different genes are transcribed. We can therefore obtain a global picture of the changes that occur in bacteria when they are treated with an antibiotic lead and deduce the likelihood of resistance emergence before the lead is further developed into a medicine.This will not only save efforts on compounds that are prone to elicit resistance but will also provide information on how to anticipate resistance and devise procedures to circumvent it before a new antibiotic is in clinical use. Genomics of the antibiotic producers One topic in which genomic research can help is the analysis of global regulatory circuits in the antibiotic-producing organisms.Many efforts have been put into the application of genetic research to increase the amount of antibiotic produced by the producer organisms. Most if not all of them have not yielded practical results. Many antibiotics are produced under suboptimal growth conditions as products of secondary metabolism. Under those conditions deviations towards the production of a single compound may severely upset the growth of the organism, resulting in a failure to increase the net production of the desired compounds. A better understanding of the regulatory circuits that operate under suboptimal and stressful conditions will allow the modification of the production of some secondary metabolites without greatly disturbing growth.
Coordinator
Vicente, Miguel Centro Nacional de Biotecnologa CSIC Campus de Cantoblanco 28049 Madrid, Spain Phone: +3491 585 4699 Fax: +3491 585 4506 Email: mvicente@cnb.uam.es Project web-site: For the book of abstracts: http://www.cnb.uam.es/~mvicente/full_book.pdf For the final report: http://www.cnb.uam.es/~mvicente/microMATRIX+cover.pdf Key words: bacteria, essential functions, regulation, gene expression, stress response, pathogenesis
Partners
Tel Aviv University, Israel ITQB Universidade Nova de Lisboa, Portugal Institute of Cell & Molecular Biology, University of Edinburgh, United Kingdom Institut Pasteur, France PROGENIKA Biopharma S.A., Spain
Acronym: micro-MATRIX Project number: LSSM-CT-2003-502801 EC contribution: 2 980 000 Instrument: Specific Support Action Duration: Four days Starting date: 17/04/2004
Diagnostics
DNA arrays can speed up the diagnosis of infections.Moreover,the use of subgenomic arrays containing suitable sets of genes will easily identify specific strains of a pathogen. Once the technology is fully developed it will be possible to design antibiotic courses specifically tailored to help an individual patient to fight against one particular infection.
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Brain, neurological and psychiatric diseases

PROMEMORIA NEWMOOD APOPIS GENADDICT EUROSCA NeuroNE BrainNetEurope II AUTISM MOLGEN SYNSCAFF EUROHEAD SPASTICMODELS NCL-models NEUROKCNQPATHIES X-ALD PainGenes GRIPANNT STRESSPROTECT INTERDEVO NeuroDisseminator EUROMEMO ESNI course 2003 FENS Forum 2004 RABRE 88 90 93 95 97 100 102 106 108 111 113 116 118 120 122 124 126 129 131 132 135 137 139
BRAIN, NEUROLOGICAL AND PSYCHIATRIC DISEASES
PROMEMORIA
From cell-cell recognition to memory formation. New strategies for the treatment of dysfunctional plasticity, learning and memory
Summary
The PROMEMORIA project focuses on the role of cell recognition processes in normal and dysfunctional plasticity, learning and memory with the aim of developing compounds with a beneficial effect on diseases involving cognitive impairment. The focus on neuronal cell adhesion molecules is novel and unique. Recent research has shown that these molecules play key roles in learning and memory.The project includes a series of subprojects focused on gene discovery, structural biology, synaptic plasticity at both the physiological and morphological level, and a number of models of deficient plasticity, learning and memory. The Consortium consists of 18 leading teams from 11 countries, of which two are new EU member states. It is composed of 14 academic partners and 4 SMEs. The Consortium contains teams specialised in genetics, protein chemistry, neurophysiology, neuroanatomy, neurobiology, animal models of learning and behavior, in vivo test systems for a very broad range of behaviour and learning phenomena. Moreover, there is a considerable expertise in drug screening and development. An efficient dynamic management structure is proposed with four key objectives:integration of research results and early identification of new findings; training of future world leaders in this research area; dissemination of results to scientists, patients and the general public; the issue of 5-10 patents securing protection and transfer to European industry of PROMEMORIA discoveries. corresponding drug targets.The study of the role of neuronal CAMs has so far been limited by technological problems and functional investigations have been difficult. However, we have recently developed the first series of peptido-mimetics of a neuronal CAM (NCAM) and thereby created a new type of compound with a tremendous promise both as regards the understanding of the functions of CAMs at the molecular level and the development of drugs with beneficial effects on synaptic plasticity on neuroregeneration. Neuronal cell adhesion molecules Neuronal CAMs are known for their involvement in brain developmental processes,and recent evidence now indicates that they also participate in synaptic alterations in connection with memory formation in adults. CAMs of particular importance include member of the Immunoglobulin-(Ig) superfamily, Cadherins and Integrins. Particularly the roles of L1 and NCAM are now well supported by experimental data.Neuronal CAMs in general are well known for their involvement in processes of relevance to neuronal plasticity such as axonal extension and guidance,cell migration,differentiation,survival, and formation of synapses. Role of CAMs in memory formation Evidence for a role of L1 and NCAM in memory formation comes from studies interfering with the functions of these molecules in different learning paradigms. Modifications of L1- and NCAMmediated cell recognition appear to be a prerequisite for the formation of stable changes in synaptic communication.These changes are probably achieved through alterations in gene expression, posttranslational modulations and turnover of the proteins.
Aim
to achieve a better understanding of the role of neuronal cell adhesion molecules CAMs in the maintenance and modulation of synaptic and network plasticity and in cortical circuitry and information processes underlying learning and memory; to develop and validate a series of suitable animal models for studies of memory function and dysfunction in diseases; to search for novel ligands and mimetics of neuronal CAMs for modulation of plasticity with the aim of developing therapeutics improving learning and memory
Background
Cognitive impairment In the western world, 6-10% of adults older than 65 years have dementia mainly due to Alzheimers disease. A large group of elderly are suffering from so-called mild cognitive impairment, a diagnostic term applied to individuals who do not meet the clinical criteria of dementia or Alzheimers disease, but who are cognitively impaired. The therapeutic possibilities for treatment of cognitive impairment are currently very limited, emphasising the profound need for development of new therapeutic modalities.A problem is the heterogeneous temporal and spatial distribution of the
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Expected results
The Consortium expects to discover new genes and proteins,identify novel pathogenic mechanisms and define new therapeutic strategies, with clearly defined deliverables: new counterreceptors (ligands) of cell adhesion molecules will be identified, key proteins will be structurally characterised and binding sites will be localised (WP 1); experts in the field of neurophysiology will establish the role of neuronal CAMs in maintenance and modulation of selected synapses and synaptic populations. Moreover, the role of CAM signaling in triggering use-dependent and/or developmental changes in circuitry will be assessed (WP 2, 3, 8); new animal models for dysfunctional plasticity will be established, validated and employed for evaluation of learning and memory under various conditions involving CAM-modulation (WP 4, 5, 6, 7); ligands will be developed interacting with the CAM binding sites, either agonistically or antagonistically, through drug screening or based on structural determinations. These studies are expected to identify novel therapeutic strategies and new therapeutic targets (WP 8); the unprecedented degree of collaboration between academic groups and biotechnology SMEs in PROMEMORIA is expected to result in a rapid translation of findings into new strong intellectual property, and subsequently into drug screening programmes (WP 10, 11); the goal-oriented network will train a younger generation of European scientists to excellence within the highly integrated research area of plasticity, learning and memory (WP 9); at least five patent applications will be filed (WP 10).
Coordinator
Prof. Bock, Elisabeth University of Copenhagen Institute of Molecular Pathology The Protein Laboratory Blegdamsvej 3C 2200 Copenhagen N, Denmark E-mail: bock@plab.ku.dk Project web-site: Under construction Key words: genetics, cell adhesion molecules, cognition, dementia, neurodegeneration, drug development
Partners
1 Ireland 2 United Kingdom 1 France 2 Germany 2 Switzerland 2 Spain 1 Poland 2 Sweden 1 Israel 2 Denmark 1 Estonia
A considerable fraction of adults will encounter impairment in learning and memory as they age, and age-related memory impairment often predates more serious neurological problems. Neurodegenerative diseases including Alzheimers disease, Parkinsons disease, motor neuron diseases, stroke and demyelinating diseases are rapidly becoming major health problems in developed countries. Moreover, neurological injuries also may lead to cognitive impairment.
Acronym: PROMEMORIA Project number: LSHM-CT-2005-512012 EC contribution: 9 700 000 Instrument: Integrated Project Duration: 48 months Starting date: 01/04/2005
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NEWMOOD
New molecules in mood disorders: a genomic, neurobiological and systems approach in animal models and human disorder
Summary
This is a major collaboration between 13 clinical and basic science groups in 10 EU countries which addresses the evident need to discover: new molecular mechanisms in the causation of depression new molecular mechanisms of effective drug-treatment. We will measure three fundamental processes underlying depression the inability to experience pleasure,excessive sensitivity to stress and negative appraisal of circumstances.This will enable us to cross-validate findings in humans and animal models. In animals (rats and mice) we will use a mixture of well-established and novel methods for inducing genetic and mild stress-related changes in the three processes.We will detect the molecular mechanisms involved by creating the NEWMOOD microarray chip and measuring changes in gene expression. Changes which are consistent across many models will become targets for new treatments. In addition we will search for neurochemical changes in how monoamine and other neurones are regulated which are shared by the models.These too will become new molecular targets. Humans with varying genetic and environmental risk factors will be compared on the three behaviours and on the brain systems and neurotransmitters responsible using functional magnetic resonance imaging.Gene-expression in the human postmortem brain will provide further validation of animal findings and targets for treatment. Furthermore, there has been a remarkable increase in the rate of suicide in young males over the last 15 years in the EU. Indeed suicide is second only to road traffic accidents as the cause of death in the 15 to 25 age band. Female gender and social and familial factors increase risk of depression but little is known about how these influences work in the brain, least of all at the molecular level. Antidepressant treatment has improved in terms of tolerability and thus treatment adherence but drugs currently in use have the same primary mechanisms of action as 30 years ago and their downstream molecular actions are obscure. Furthermore, at most 65% of new episodes respond to drug-treatment and chronic, treatment-resistant depression is a major health burden.
Aim
The aim of this proposal is to combine new functional genomic technologies with chemical analysis in an integrated multidisciplinary approach both to exploit hitherto overlooked genetic resources for new antibiotics and, secondly, develop generic superhosts to produce these new antibiotics in high yields. ActinoGEN proposes three parallel objectives to discover and develop new antibiotics based on exploiting the genetic resources of actinomycetes, hitherto the major source of existing antimicrobials.The first of these is to activate cryptic antibiotic biosynthetic pathways. Recent genome sequencing projects have revealed a genetic potential for actinomycetes to produce many more antibiotics than previously recognised.ActinoGEN will explore how different cryptic pathways can be activated and then determine the structures and activities of the resulting new antimicrobials. The second approach will rely on the discovery of new antibiotic biosynthetic pathways from diverse actinomycetes. The number of actinomycete species that have been isolated to date represents a small fraction of the total in the environment. ActinoGEN will exploit the untapped genetic resource of as yet uncultured species to obtain antibiotic biosynthetic gene clusters that can direct synthesis of new antimicrobials. A third route to new antimicrobials is by combinatorial biosynthesis. Biosynthetic genes from both new and existing pathways will be combined to direct synthesis of new antibiotics with predicted structures. The design of new hybrid molecules will be related to improving antimicrobial activity. A fourth major aim, underpinning the Drug Discovery objectives, is the engineering of generic Superhosts for antibiotic production.A ratelimiting step to developing a new antibiotic is yield improvement. Post-genomic analysis permits, for the first time, a concerted and holistic approach to engineering generic Superhosts for use in the production of high yields of a wide variety of antibiotics.As part of ActinoGEN, this complementary activity is vital to greatly accelerate the discovery and development of new drugs.
Background
Unipolar major depression is common and a leading cause of morbidity and mortality.In developed countries it is twice as common in women as men, affecting 20% of women at some time in life.The global burden of disease survey found it will be the fourth most prevalent cause of disability-adjusted life years, accounting for about 20% of the burden of disease (Murray 1997 Lancet 349:1436-1442). This is greater than the burden of common causes of death such as cardiovascular disease. In addition to its economic consequences, depression is a direct cause of death through suicide. There are important cohort effects the age of onset of depression is steadily decreasing each decade and it is no longer a disease of middle age.
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Expected results
The overarching aims are to identify: new molecular mechanisms in the causation of depression, specifically new candidate genes for diagnosis, prognosis and treatment choice; new molecular mechanisms of effective drug treatment, specifically new molecular targets for antidepressant drugs and novel candidate drug treatments. The technical aims are to: create a web-based core data-set of behavioural and neurobiological variables common to human and animal vulnerability to the depression endophenotype; create a new tool for research in depression: the NEWMOOD Depression microarrays; define a human pharmaco - fMRI signature for antidepressant efficacy; disseminate new and harmonised standards of research in affective disorders.
Coordinator
Prof. Deakin, Bill University of Manchester Neuroscience and Psychiatry Unit Room G.907, Stopford Building Oxford Road Manchester, M13 9PT, United Kingdom Phone: +44 161 275 7427 Fax: +44 161 275 7429 E-mail: bill.deakin@man.ac.uk Project web-site: NEWMOOD website within http://projectplace.com A public website will be created. Key words: depression, stress, candidate genes, human, animal models, brain, neurochemical, neurobiological, neurotransmitters, antidepressants, 5-HT
Expected results
the identification of differences in gene expression that are consistent across a wide range of entirely different animal models; the detection of altered gene expression, neurochemical, neurophysiological and neuroendocrine regulatory mechanisms, which are common to a range of genetic, developmental and mechanistic animal models of vulnerability; the identification of candidate genes for diagnosis, prognosis and treatment choice; a better understanding of the molecular mechanisms of depression and other mood disorders; a greater understanding of the nature and extent of genetic predisposition in depression.
Partners
Dr Lanfumey, Laurence INSERM U 288 Facult de Mdecine Piti-Salptrire Paris, France Prof. Corradetti, Renato Universit degli Studi di Firenze, Dipartimento di Farmacologia Preclinica e Clinica Florence, Italy Prof. Lesch, Klaus Peter University of Wrzburg Department of Psychiatry and Psychotherapy Wrzburg, Germany Prof. Maldonado, Rafael Universitat Pompeu Fabra Laboratory of Neuropharmacology Department of Experimental Sciences and Health Barcelona, Spain
the identification of new targets for drug therapies; the development of novel drug treatments; progress towards drug regimes tailor-made to suit individuals; ultimately, to reduce the overall morbidity and mortality due to depression and other mood disorders.
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Prof. Harro, Jaanus University of Tartu Department of Psychology Estonian Centre of Behavioural and Health Sciences Tartu, Estonia Prof. Steinbusch, Harry University of Maastricht Division Neuroscience Maastricht,The Netherlands Prof. Bagdy, Gyorgy Head of Laboratory of Neurochemistry and Experimental Medicine National Institute of Psychiatry and Neurology, Budapest, Hungary Dr Kelly, Paul A T University of Edinburgh Division of Clinical Neurosciences School of Molecular & Clinical Medicine Western General Hospital Edinburgh, United Kingdom Dr Sharp,Trevor University of Oxford Department of Pharmacology Oxford, United Kingdom
Dr Hkfelt,Tomas Karolinska Institutet, Department of Neuroscience B3:4 Stockholm, Sweden Prof. Del Ro, Joaqun University of Navarra Medical School Department of Pharmacology Pamplona, Spain Dr Swiergiel,Artur H Polish Academy of Sciences ("IGAB") Institute of Genetics and Animal Breeding Poland
Acronym: NEWMOOD Project number: LSHM-CT-2004-503474 EC contribution: 7 200 000 Instrument: Integrated Project Duration: 60 months Starting date: 01/05/2004
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APOPIS
Abnormal proteins in the pathogenesis of neurodegenerative disorders

Summary
Degenerative disorders of the nervous system including Alzheimers and Parkin-sons are among the most de-bilitat-ing illnesses. There is currently no treatment that can halt or prevent,let alone reverse nerve cell degeneration. One hallmark common to these dis-orders is the deposition of abnormal protein aggregates. APOPIS is designed to elucidate the role of abnormal proteins in the pathogenesis of neurodegenerative disorders and to develop methods for early diagnosis and treatment of these devastating diseases. Senile plaque associated markers in SweArc APP transgenic mice. Astrogliosis (strongly stained) around senile plaques (white arrows). Lars Nilsson, Uppsala University
Background
The APOPIS programme is based on the information generated by the recently completed sequencing of the human genome. APOPIS will make use of this information and employ state-of-the-art technologies in functional genomics, proteomics, bioinformatics, and neuroimaging, which will be combined with more traditional approaches such as epidemiological studies, transgenic model organisms and combinatorial chemistry in order to quickly identify putative target genes and lead compounds for drug discovery.
Aim
The first goal of APOPIS is to improve the understanding of the pathogenic mechanisms involved in neurodegenerative diseases applying several complementary model systems and methodologies.The second goal is to advance the early clinical detection of these diseases, thus providing a theoretical chance for clinical treatment before it is too late. The third goal of APOPIS is the development of effective strategies and efficacious drugs for the treatment and the prevention of these diseases.
Expected results
APOPIS is designed to elucidate disease mechanisms and to translate the results into clinically useful products. Protein deposits seem to play an essential but as yet poorly understood role in disease progression. Therefore, by comparing a whole set of neurodegenerative diseases afflicting different areas of the brain, it is expected to gain insight into common features in the underlying disease mechanisms, for instance, the causative agents or events for abnormal protein aggregation.These breakthrough discoveries will lead to the identification of pharmacological targets creating the basis for an effective drug design to halt the cascades involved in the disease processes.
The advancement in clinical studies will lead to improved tools for the early and differential diagnosis of neurodegenerative diseases.Immediate and reliable detection of neurodegenerative disorders is a prerequisite for efficient clinical studies and finally for a successful treatment of the disease. Intellectual property rights will be protected by patent applications to ensure the seamless design and development of efficacious and safe clinical products for the treatment and the prevention of neurodegenerative diseases.
Senile plaque pathology differently stained in SweArc APP transgenic mice (A, B). Lars Nilsson, Uppsala University
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Coordinator
Prof.Adlkofer, Franz VERUM Foundation Pettenkoferstr. 33 80336 Munich, Germany Phone: +49 89 5309880 Fax: +49 89 53098829 E-mail: prof.adlkofer@verum-foundation.de Project web-site: www.verum-foundation.de/apopis Key words: early diagnosis, genetics, neurodegenerative disorders, pathogenesis, protein aggregation, therapy
Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Sweden Institute of Biochemistry, Swiss Federal Institute for Technology, Zurich, Switzerland Department of Neuroscience, Universita Vita-Salute San Raffaele, Italy Istituto de Recerca Biomedica de Barcelona, Parc Cientific de Barcelona, Spain Phone: +34 9340 34902, fax: +34 9340 37225 Division of Psychiatry Research, University of Zurich, Switzerland Clinic of Neurology, University of Marburg, Germany EVOTEC NeuroSciences GmbH, Hamburg, Germany Dementia Research Centre/The National Hospital for Neurology and Neurosurgery, University College London, United Kingdom School of Medicine, University of Genova, Italy Department of Biochemistry at the University of Naples, Italy Institut fr Organische Chemie, Universitaet Darmstadt, Germany Institute for Clinical Neurobiology, University of Wrzburg, Germany Structures & Biocomputing, European Molecular Biology Laboratory, Heidelberg, Germany Department of Neurology PO 41/Institute of Psychiatry, Kings College London, United Kingdom MPI of Molecular Cell Biology and Genetics, Max Planck Society for the Advancement of Science, Dresden, Germany Institute of Biochemistry, University of Zurich, Switzerland Biological Chemistry/Institute of Life Sciences, The Hebrew University of Jerusalem, Israel Department of Neurology, University of Cambridge, United Kingdom Department of Biosciences, University of Kent at Canterbury, United Kingdom Department of Molecular Genetics at the University of Antwerp, Flanders Interuniversitary Institute for Biotechnology,Antwerp, Belgium Neuroproteomics Research, Max Delbrueck Center for Molecular Medicine, Berlin, Germany
Partners
Institute of Neurosciences, Swiss Federal Institute of Technology Lausanne (EPFL), Switzerland Institute of Neuropathology, University Hospital Zurich, Switzerland Bioinformatics and Molecular Genetics, University of Freiburg, Germany Wallenberg Neuroscience Centre, Lund University, Sweden Groupe Hospitalier Piti-Salptrire, Institut Nationale de la Sant et de la Recherche Mdicale (INSERM), Paris, France Universit de Lille 2, France Institut de Pharmacologie Molculaire et Cellulaire, Centre National de la Recherche Scientifique,Valbonne, France Centro de Biologia Celular/Laboratory of Neuroscience, Universidade de Aveiro, Portugal Flanders Interuniversitary Institute for Biotechnoology, Center for Human Genetics, Leuven, Belgium Cavalieri Ottolenghi Scientific Institute, Fondazione Cavalieri Ottolenghi, Italy Cellzome AG, Heidelberg, Germany Department of Human and Animal Physiology, University of Athens, Greece Department of Biochemistry, University of Munich, Germany Division of Psychiatry Research, University of Zurich, Switzerland Department of Neuropathology, University of Basel, Switzerland MPI for Neurobiology, Max Planck Society for the Advancement of Science, Martinsried, Germany Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology,Warsaw, Poland
Acronym: APOPIS Project number: LSHM-CT-2003-503330 EC contribution: 8 995 518.39 Instrument: Integrated Project Duration: 36 months Starting date: 01/01/2004
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GENADDICT
Genomics, mechanisms and treatment of addiction

Summary
Addiction is a brain disease, common in Europe, with deleterious consequences on individual physical and psychological health,and serious societal and economic consequences through criminality and violence, decreased productivity and increased healthcare costs. In every family, in a lifetime one can identify someone who has suffered from addiction. Alcohol, nicotine or illicit drug use affects many people. Over 20 years there has been little advance in the drug treatment for addiction, with most new treatments addressing physical drug withdrawal rather than treating drug craving and relapse.The contribution of genetic influences to addiction liability has been recently recognised but the identification of genetic risk factors and genes involved in the molecular basis of addiction is a new major challenge for the post-genomic era.This project is a collaboration between basic science groups, one SME and a leading biotechnology company devoted to human studies on the role of genes in complex diseases. This public-private partnership brings together a highly innovative genealogical-led human genetics approach and a team of researchers with Europes best genomic mouse models.The core of the research effort will be the identification of genes associated with drug addiction using an unbiased genome-wide approach. The strong environmental component in the etiology of drug addiction has presented a particularly difficult problem for genetic studies of this brain disorder in the past.The groups of this consortium propose to meet this difficult challenge by combining powerful animal genetics and gene profiling strategies with a human genetic approach that is relatively resistant to environmental modifications of the drug addiction phenotype. Genes identified in this project will help to elucidate dysfunction of genetic pathways in the addicted brain and provide new targets for the development of novel therapies. are responsible for predisposition to addiction.Their complementary molecular genetics and neuroscience expertise provides a critical mass of expertise to create a foundation of genetic information using stateof-the-art mouse models. These academic groups have linked with an Icelandic company,Decode Genetics,which is at the forefront in Europe in the field of complex genetics in man.They bring a human research contribution to this Integrated Project of equivalent capacity to the animal studies.The human experiments bring a unique and well-defined human population for large-scale gene analysis that will integrate with genes identified in the mouse programme.
Aim
The aim of the Integrated Project is to discover: new candidate genes that are involved in addiction using human and mouse approaches; new genetic mechanisms that are involved in addiction; new molecular targets for the treatment of addiction. The human studies in this project will be carried out by Decode Genetics in Iceland, using a genealogical approach to gene isolation, which is central to their success in mapping genes for complex disorders. It is based on taking a list of patients with the phenotype broadly defined, in this case addiction and subtypes of addiction, analysing it using the genealogy database to identify families, who will subsequently be recruited for a genome-wide scan for linkage. The genealogical analysis of large cohorts not only detects how individuals segregate into large families but also provides information on the relationship between phenotypes. The human genetic component of this project will be complemented by linkage studies in mice.This platform will generate a large cohort of phenotypically well-characterised mice from specifically designed genetic crosses for linkage analysis.This analysis will provide chromosomal loci and genes that contribute to drug vulnerability in animal models. Subsequent human association studies will then help to determine if these genes also play a role in drug addiction in humans. This project also brings together groups in Europe that have developed gene knockout animals of both the opioid and dopamine systems in the brain.These systems are considered to be key players involved in the mechanisms of addictive drugs and thus provide us with unique animal model to identify genes involved in addictive processes. This project extends the use of genetic models to identify genes that contribute to all components of addictive behaviour and also to study the fundamental mechanistic basis of addiction. The key role of the opioid and dopamine systems in addiction enables us to use the knockout models to identify, using gene expression studies, potential candidate genes for addiction. In addition we propose to develop sitespecific and inducible knockout animals, which will not only provide unique animal models for refined identification of addiction genes, but will also provide further fundamental information on addiction mechanisms.
Background
This is a major focused collaboration between 12 partners across Europe including one leading genetics company and an SME developed from the research success of one of the academic groups in this partnership.The groups are spread across seven EU countries,including two recently incorporated countries (Hungary and Poland) and one associated country (Iceland). It is an integrated multidisciplinary project bringing together genome-wide gene identification studies in addicted patients with genomic studies in the mouse, to identify common genes involved in addiction. The animal experiments bring together seven leaders in genetic studies of addiction in Europe that have, and will further develop, a unique collection of gene knockout animals that can be used to understand common underlying genetic mechanisms that
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Expected results
The project will carry out genotyping and linkage analysis of familial material to identify genes linked to addiction to individual substances, and to identify gender difference in gene specific linkage, as well as identifying genetic links with specific psychiatric phenotypes. The project will dissect out potential genes that confer susceptibility to addiction by identifying candidate genes from animal studies, and identifying genotype-phenotype relationships for addiction. The project will identify genes induced by addictive substances by expression profiling in wild-type and gene knockout mice, and by expression profiling in strains of mice with altered sensitivity to morphine or cannabionoids. The project will identify if anxiety or stress are associated with drug abuse preference by phenotyping and quantitative trait loci analysis, and by evaluation of candidate genes for association with drug addiction in humans and animal models. The project expects to create conditional knockout mice with deletions of either mu, D2 and proenkephalin genes and will verify the neurochemical disruption of these animals. In addition, the project will develop site-specific knockout mice, to delete receptors and peptides in specific addiction related brain areas, and to analyse behavioural and neurochemical responses of site-specific deletion. In addition,we expect to characterise the involvement of opioid, dopamine and cannabinoid receptors and opioid peptides in the addictive properties of nicotine studying behavioural responses to nicotine in wild-type and knockout animals. Further, we expect to characterise the role of specific opioid, dopamine and cannabinoid genes in addictive neurochemistry by studying neurotransmitter release in the nucleus accumbens of gene knockout mice,studying G-protein receptor activation in gene knockout mice,and by studying electrophysiological changes in gene knockout mice.
Coordinator
Prof. Kitchen, Ian University of Surrey School of Biomedical and Molecular Sciences Guildford GU2 7XH, United Kingdom Phone: +44 1483 689734 Fax: +44 1483 576978 E-mail: i.kitchen@surrey.ac.uk Project web-site: To be developed. Key words: Addiction, genomics, drug abuse, gene knockout, genealogy, alcoholism, opiates, dopamine
Partners
Prof. Maldonado, Rafael University Pompeu Fabra, Laboratory of Neuropharmacology, Department of Experimental Sciences and Health, Barcelona, Spain Prof. Kieffer, Brigitte L Institut de Gntique et de Biologie Molculaire et Cellulaire CNRS/INSERM/ULP Illkirch, France Dr Borrelli, Emiliana Institut de Gntique et de Biologie Molculaire et Cellulaire Directeur de Recherche, INSERM Illkirch, France Prof. Zimmer,Andreas Life & Brain GmbH Laboratory of Molecular Neurobiology Bonn, Germany Prof. Przewlocki, Ryszard Institute of Pharmacology Polish Academy of Sciences Department of Molecular Neuropharmacology Krakow, Poland Prof. Freund,Tams F Hungarian Academy of Sciences Institute of Experimental Medicine Budapest, Hungary Dr Thorgeirsson,Thorgeir E Decode ehf, Reykjavik, Iceland
The potential of a fuller understanding of the genomics of addiction is two-fold. Firstly, the opportunity to develop diagnostic tests to identify an individuals susceptibility to become addicted to drugs,gives a chance to protect vulnerable individuals more effectively. Secondly, new treatments for drug addiction which result from understanding the genetics of addiction have the potential to reduce the economic cost of addiction,which impacts heavily on the sectors of health,work, social services and the judicial system. The ultimate objective of this Integrated Project is to provide new knowledge that can be used by the participants or by European pharmaceutical companies to develop new drugs for the treatment of both drug craving and relapse, which are core features of addictive disorders, or for providing new drugs for treating physical dependence and withdrawal from drugs of addiction. The scientific knowledge gathered will allow the consortium to identify specific genetic alterations in addicted patients and to develop novel treatments tailored to the modulation of addictive processes that are under genetic control. In addition, the production of novel knockout strains of mice with site-specific and temporally regulated mutations represents a major technical advance in gene manipulation in animals. These models will enrich the scientific community and provide new means to study the roles of selected genes in not only addiction but also several other disorders of mood and pathological pain states.
Acronym: GENADDICT Project number: LSHM-CT-2004-005166 EC contribution: 8 100 000 Instrument: Integrated Project Duration: 60 months Starting date: 01/01/2005
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EUROSCA
European Integrated Project on spinocerebellar ataxias (EUROSCA): Pathogenesis, genetics, animal models and therapy
Summary
Twenty two European groups from nine countries with an excellent reputation of clinical, clinical-genetic and basic research on spinocerebellar ataxias (SCA) will aim at developing a treatment for patients suffering from this rare neurodegenerative disease.To reach this goal, an international standard on the clinical evaluation in form of a Core Assessment Programme for Interventional Therapies of SCA (CAPIT-SCA) will be developed.The generation of the worlds largest collection of information on SCA, the European SCA Registry (EUROSCA-R), will ensure standardised data acquisition and facilitate continuous recruitment of SCA patients throughout Europe. The potential to include all larger European SCA families into linkage analysis will lead to the identification of new SCA loci and to the cloning of novel ataxia genes. Genotype-phenotype correlations will follow. Such a combined effort will offer a systematic large-scale search for genetic modifier factors in SCA. EUROSCA will also implement strong research projects to generate and characterise cellular and transgenic models, which will allow a more defined study of the pathogenesis and will serve as a tool for first therapeutic studies. Five core facilities and training programmes will complement research efforts and clinical work. Deciphering these mechanisms will lead to the development of drugs preventing protein aggregation, neuronal death and stopping or delaying the progression of these diseases.
Aim
Due to the low prevalence of SCA and because of its broad genetic heterogeneity, it is difficult to collect large numbers of patients. Therefore the characterisation of the underlying pathogenetic factors and the potential to initiate large therapeutic studies are limited.This project will implement a network structure spanning nine European countries to collect the worlds largest set of genetically defined patients (European SCA registry = EUROSCAR). We will characterise these patients based on a novel set of clinical data using clinical rating scales, structural imaging, and electrophysiology to generate the largest and best characterised SCA patient collection (Core Assessment Program for Interventional Therapies = CAPIT-SCA). The advantage of having SCA families linked to a specific chromosomal region for which the genetic cause has not been defined yet (SCA11, SCA13, SCA14, SCA21) will be further strengthened by providing additional families for which genetic linkage is unknown. It is anticipated that some genes will be cloned by EUROSCA within the next years. For the patients themselves an oriented information network (EUROSCA web portal) will be established allowing easier contact with specialised clinics of neurology. The scientific research objectives will concentrate on the most frequent and important SCA subtypes (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) to decipher the pathogenesis of these diseases, to generate animal and cellular models, and to develop therapeutic strategies.All research groups will get major support by highly specialised core facilities to produce poly- and monoclonal antibodies, to generate Drosophila models, to perform complex proteome and transcriptome analyses and to decipher interacting proteins.
Background
Spinocerebellar ataxias (SCAs) consist of a highly heterogeneous group of progressive movement disorders usually manifesting in the third to fourth decade of life and commonly lead to death after a long duration of suffering for more than 20 years. The disease is inherited as an autosomal dominant trait. Since a cure is currently not available, the development of drugs for SCA will have great impact.The prevalence of SCA in Europe is not well known but is assumed to be less than 1:10 000. The high clinical and genetic heterogeneity is manifested by the description of 21 SCA associated loci and there are several lines of evidence of further loci implicated. For nine of the SCA subtypes the underlying mutations have been defined and shown to be caused by a trinucleotide repeat expansion, most of them within the coding region of the respective gene and encoding a polyglutamine chain. Pathohistologically, intranuclear inclusions are detected in the affected regions of the brain. However, the pathomechanism(s) underlying neuronal cell death and the region specificity of the neurodegeneration remain unknown.
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EUROSCA consists of four sub-structures:

(i) Generation of the world largest patient DNA registry (EUROSCA-R), which will allow extraordinary opportunities to map novel gene loci, to identify novel SCA genes (SCA4, SCA11, SCA13, SCA14, and SCA21), and to study modifier genes of the age at onset (in particular of SCA1, SCA2, and SCA3). (ii) Development of the first Unified Ataxia Rating Scale (UARS), which will be used to generate a Core Assessment Programme for Interventional Therapies (CAPIT-SCA). CAPIT-SCA is important to measure disease progression in SCA, one of the major steps to objectively allow differentiation of genetically different SCA subtypes at the clinical level and one prerequisite to monitor efficacy in clinical studies. (iii) Pathogenesis of the most common SCA sub-forms (SCA1, SCA2, SCA3, SCA7, SCA17).To resolve these questions cellular and mouse models for most of the SCAs have already been generated (SCA1, SCA2, SCA3, SCA7); others are being prepared (SCA17, and Drosophila models).These models will be used in initial therapeutic studies. (iv) Research groups are strongly supported by five core facilities to generate monoclonal and polyclonal antibodies, to generate Drosophila models, to analyse the transcriptome and the proteome and to build networks of interacting proteins.
Coordinator
Prof. Rie, Olaf Eberhard Karls-Universitaet Tuebingen Department of Medical Genetics Calwerstrae 7 72076 Tuebingen, Germany E-mail: olaf.riess@med.uni-tuebingen.de Project web-site: http://www.eurosca.org/ Key words: brain research, degenerative disease, rare disease, neurodegeneration, spinocerebellar ataxia, trinucleotide repeat disorders
Partners
Institute of Child Health London, University College, London, United Kingdom Klinik und Poliklinik fr Neurologie, Universittsklinikum, Bonn, Germany Hpital de la Salptrire, Institut National de la Sant et de la Recherche Mdicale, Paris, France Department of Biochemistry & Genetics,Istituto Nazionale Neurologico Carlo Besta, Milan, Italy Cambridge Institute for Medical Research, University of Cambridge, United Kingdom Department of Neurology, University Medical Center Nijmegen,The Netherlands Department of Neurology, Universit Libre de Bruxelles, Belgium Department of Genetics, Institute of Psychiatry and Neurology,Warsaw, Poland Department of Medical Genetics and Child Development, University of Pcs, Hungary
Expected results
worlds largest DNA registry for SCA patients (EUROSCA-R); core Assessment Program for Interventional Therapies (CAPITSCA); new epidemiological data; risk prediction, modifier genes; defining new gene loci, disease gene cloning; disease models for SCA1, 2, 3, 6, 7, and 17; defining the pathogenesis common to polyQ type SCA; development of five potential drugs and testing in animal models.
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Service of Neurology, Servio Cntabro de Salud, Santander, Spain Department of Molecular Pathogenesis, University of London, Institute of Neurology, London, United Kingdom Ruhr-University Bochum,Department of Neurology,St.Josef Hospital, Bochum, Germany Neurogen Frankfurt, Johann Wolfgang von Goethe University, Frankfurt/Main, Germany Institut fr Humangenetik, Universitt Lbeck, Germany Institut Jacques Monod, Centre National de la Recherche Scientifique Paris, France Neuroproteomics, Max Delbrck Centrum for Molecular Medicine, Berlin, Germany Centre European de Recherche en Biologie et Medecine, IGBMC Illkirch, France Department of Crystallography, Birkbeck College, University of London, United Kingdom Molecular Structure Division,National Institute for Medical Research, London, United Kingdom
Acronym: EUROSCA Project number: LSHM-CT-2003-503304 EC contribution: 9 450 000 Instrument: Integrated Project Duration: 60 months Starting date: 01/01/2004
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NeuroNE
Molecular mechanisms of neuronal degeneration: from cell biology to the clinic

Summary
NeuroNE is Europes premier research network for the creation of novel therapeutic approaches to neurodegenerative disease and neurotrauma,which represent an urgent socio-economic and human need.The NeuroNE consortium (22 academic groups,five SMEs and one management partner in nine different countries) is taking a multidisciplinary (functional genomics and proteomics,physiology,chemistry, clinical studies) and multi-faceted (disease mechanisms, biology of cell death and survival,regeneration mechanisms,high-throughput screening, gene- and cell-based therapies) approach to this problem. Among the neurodegenerative diseases, the network focuses on Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Spinal cord injury (SCI) will be the main model for neurotrauma.NeuroNE brings together investigators from different backgrounds (basic scientists,active clinicians and therapeutically-oriented SMEs) to work at all levels on the target diseases using the methods of post-genomic science, molecular and cell biology, animal models, therapeutic strategies and clinical studies. Professional project management provides efficient integration, realisation of scientific objectives and knowledge management. The scientific infrastructure of the network includes shared NeuroNE-funded core facilities in seven centres.The network has employed a team of scientists based in the participating laboratories who will conduct research and form collaborations among the different participants.The network has a programme of scientific meetings that will consist of three major international plenary meetings and ten scientific workshops on specific topics.To feed back the benefits of integration into EU society, the network is working with patient organisations, identified associated research groups who will benefit immediately from our infrastructures, and has opened network meetings to identified scientists from emerging research centres. Predicted number of Europeans affected by Alzheimer's disease. From Wancata et al., 2003
Expected results
The mechanisms involved in any neurodegenerative disease, in neurotrauma exhibit some unique properties and many shared elements. A limited number of basic technologies need to be developed which will have an impact in many of these conditions.However,to be competitive, individual research groups usually focus on one particular disease. One major impact of NeuroNE will be to accelerate the pace of discoveries in neurodegeneration and neurotrauma by pooling expertise and resources, and focus on cross-disease and cross-discipline relations. Europe is currently home to some of the leading scientific groups worldwide in the field of neurodegenerative diseases and neurotrauma. The generation of a network including these groups will generate major synergies, further enhancing the competitiveness of European science and biotechnology in these areas, and feeding forward into the development of new treatments by European pharmaceutical companies.
Aim
Neurodegenerative diseases and neurotrauma represent one of the greatest clinical and societal challenges of the coming century. As the average age of our population increases,the numbers affected by these diseases of the nervous system will mushroom. The NeuroNE consortium is addressing this problem by designing a long-term multidisciplinary approach based on recent progress in the field of neuronal degeneration and death together with a range of cuttingedge therapeutic strategies.
Background
In the field of damage and repair of the nervous system Europe possesses scientific groups at least equal to those in other parts of the world. However their effectiveness is limited by fragmentation, lack of access to research resources, lack of clinical testing tools, lack of integration of effort between large, medium and small industrial companies and a fragmented intellectual property environment.The NeuroNE network brings together actors involved at all levels (from basic research to clinical studies and drug development) in studying many aspects of the problem (different diseases, different biological phenomena, different therapeutic
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strategies) in many countries. Together the members of the network will form an enterprise, integrated from basic science to clinical science to industry. Effective treatments for most of the diseases targeted by the network have yet to emerge. The NeuroNE network and its collaborators will accelerate the development of these treatments, which, because of the large number of patients affected by its target diseases, will be pharmaceuticals of great financial value.
Coordinator
Prof. Fawcett, James UNICAM Cambridge Centre for Brain Repair E.D. Building Robinson Way Cambridge CB2 2PY, United Kingdom Phone: + 44 1223 33 11 88 Fax: + 44 1223 33 11 74 E-mail: jf108@cam.ac.uk Project web-site: http://neurone.nuxit.net/ Key words: neurodegenerative diseases, neurotrauma, translational research, network of excellence
The overall task of the network is to create within the European Union the conditions for emergence of novel mechanism-based therapeutic approaches to neurodegenerative disease and neurotrauma. The NeuroNE scientists are convinced that research on the basic mechanisms of these diseases will help to identify pharmacological targets that will be required for the development of effective drugs for the treatment and prevention of neurodegenerative diseases. The combination of clinical groups with academic laboratories and biotech companies specialised in the field is unique on this scale in Europe, and can challenge the best elsewhere. It will form the basis for future translation of clinically relevant basic research into the clinics. Because of the growing importance of these diseases for our ageing populations, these advances will have a substantial impact, both socially and economically.
Partners
School of Life Sciences, Institute of Neurosciences - LEN, Lausanne, Switzerland Interdisciplinary Center for Neurosciences, Neurobiology, Universitt Heidelberg, Germany Center for Neurological Medicine, Neurology, University of Gttingen, Germany Division of Neurobiology, Lund, Sweden FMI, Basel, Switzerland Department of Pharmacological Sciences, University of Milan, Italy TECHNION, Rappaport Institute, Haifa, Israel Department of Medical Research and ImaGene Program, Service Hospitalier Frdric Joliot, Orsay, France INSERM, IBDM, Marseille, France Ludwig-Maximilians-University,Adolf-Butenandt-Institute, Department of Biochemistry, Munich, Germany Karolinska Institute, Department of Neuroscience, Division of Molecular Neurobiology, Stockholm, Sweden Department of Basic Neuroscience, Centre Medical Universitaire, Geneva, Switzerland Max-Planck Institute of Neurobiology, Department of Molecular Neurobiology, Munich-Martinsried, Germany Neurologische Klinik, Universitt Ulm, Germany Department of Neurology, Institute of Psychiatry London, United Kingdom Department of Human Genetics, Catholic University of Leuven, Belgium National Center for Biotechnology, CNB-C.S.I.C., Madrid, Spain Brain Research Institute, University of Zurich, Switzerland Rita Levi Montalcini Center for Brain Repair, Neuroscience Department,Turin, Italy IBDM, Campus de Luminy, Marseille, France Venetian Institute for Molecular Medicine, Padova, Italy TROPHOS SA, Marseille, France XANTOS Biomedicine AG, Munich,Germany GENETRIX, Madrid, Spain PHARMAXON, Marseille, France MEMOREC Biotec GmbH, Cologne, Germany Inserm Transfert, Paris, France
Paired helical filament extracted from an Alzheimer's disease brain immunolabelled with an anti-tau antibody.With the courtesy of Dr. Marias Gracia Spillantini
Acronym: NeuroNE Project number: LSHM-CT-2004-512039 EC contribution: 8 300 000 Instrument: Network of Excellence Duration: 48 months Starting date: 01/01/2005
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BrainNetEurope II
Network of European brain and tissue banks for clinical and basic neuroscience
Summary
BrainNet Europe II is a network of 19 established brain banks across Europe. Having established a network of ten brain banks in preparation for BrainNet Europe II we now aim to integrate new members, to spread excellence in collecting human high-quality post-mortem brain tissue and to foster research in the cellular and molecular basis of neurological and mental disorders and diseases, gender aspects and the ageing process. The main objectives of BrainNet Europe II are: 1) to acquire and distribute wellcharacterised and high-quality tissues for basic research in neuroscience; 2) to provide a basis and quality control system for RTD projects dealing with clinical or epidemiological aspects of neurological and psychiatric diseases; 3) to standardise and harmonise neuropathological diagnosis; 4) to increase the awareness of standardised neuropathological and clinical diagnosis in neurology and psychiatry at a European level; 5) to develop gold standards for tissue handling, safety aspects, quality control and ethics.These standards will be the basis for using human post-mortem brain tissue in new investigative techniques such as expression profiling and proteomics; 6) to contribute to training and exchange of neuroscientists; 7) to use modern means of information technology to exchange data within the network, to spread excellence and to disseminate information to the general public. These objectives will be reached by establishing a rigorous decisionmaking and management system resting on the members of the Project Coordination Committee and assisted by an SME accountant company. Diseases of high frequency and outstanding medical and social importance such as Alzheimer's,Parkinson's,motoneuron disease,prion diseases, multiple sclerosis, schizophrenia and affective disorders will be the focus of the network. In addition we will contribute to research in rare diseases, a research branch which can only be worked on successfully on an international European context.
Graphical presentation showing the interdependencies of the components of activities.WP, workpackage
Background
In an era of rapidly growing knowledge about the biochemistry of the brain, increasing insights into the genetics of brain diseases and a greater understanding of functional anatomy through various imaging techniques, there is an increasing need for brain and tissue banking, i.e.the collection of brain tissue from well-characterised and diagnosed patients.The reasons for this need are evident.While we collect ever more data and details about the biochemistry, molecular biology and physiology of nerve cells in culture or even in functioning animal brains, while we can biochemically characterise the cell biological processes involved in some of the notorious neurological and psychiatric diseases, there is still no clear picture emerging that would explain the relation of single biochemical findings and the pathophysiology or clinical progression of human brain disease. Brain banking will not by itself solve all these problems.However,together with modern clinical techniques, including brain imaging on the one side and molecular biology, genetics and biochemistry on the other, brain banking is at
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the interface of clinical and basic research on the brain and may therefore contribute to both. As systematic investigations have shown, more than 20% of idiopathic Parkinson's disease cases or even more of the clinical diagnoses in these diseases are in strong disaccord with post-mortem neuropathological diagnosis (Hughes et al.J Neurol Neurosurg Psychiatr, 1992, 55:181).This is a serious problem of quality control in modern medicine not restricted to Parkinson's disease. It is a particular problem in an era in which powerful therapeutic tools have become available but autopsy rates and quality control are declining. Establishing a network of brain banking will serve several purposes: first, to improve diagnosis and quality in neurology and psychiatry and second,to give an impetus to brain research.The network will contain clinical data and will in the future incorporate genetic and imaging information. Future activities that go beyond our immediate plans will show how much BrainNet Europe II will eventually be able to contribute to clinical and basic brain research. Diagnostic criteria as well as tissue handling procedures and preservation techniques are related to scientific progress and thus will change over time.It does not appear realistic to assume that once these procedural questions have found solutions they will be permanent.Yearly consensus conferences will be held to keep up with scientific progress and to adjust criteria and procedures accordingly.
technology. Many of the fundamental aspects of brain banking such as Ethics in Brain Banking are in a state of permanent change as the integration of European countries and culture progresses. These themes therefore are in need of continual updates. With the advent of novel molecular biological technologies such as mass spectrometry, expression profiling, proteomics and (functional) genomics and their simplified application in pathology and neuropathology, it is now timely to harness these technologies for brain tissue research. This in turn requires that we set standards concerning the quality of tissues to be used for the application of certain technologies. This consortium of brain banks in Europe assembles the critical mass necessary to tackle brain banking in the post-genomic era. In particular we will approach the following areas: 1) managerial and ethical problems specific to brain banking. This includes setting standards for safety in brain banking, agreeing on and using neuropathological criteria, performing technical and diagnostic quality control exercises. 2) Brain Bank specific methodological research. This entails setting standards for working with human brain tissue using modern technologies such as laser capture microscopy,mass spectrometry, expression profiling etc.Taken together this will be the basis for research into human brain diseases using various heuristic and hypothesis-driven approaches. 3) spreading of excellence beyond the network by using conventional publication in the scientific literature, giving talks at international meetings in the neurosciences and using electronic media.
Aim
Brain diseases such as Alzheimer's and Parkinson's disease and psychiatric disorders such as schizophrenia and major depression are among the most devastating and most common illnesses in our modern-day world.With increasing life expectancy the aging nervous system and its diseases are looming large at the beginning of the new millennium. Numerous local and multinational research projects in clinical and theoretical neuroscience are under way to take on the challenge.Brain and tissue banks have been set up in many institutions of member states of the European Union in order to support research projects on the biology of brain disease.It appears,however,that these efforts have long been disparate. Integration of European brain banks has been begun in a collaboration of ten brain banks in the 5th Framework Programme and is growing but needs further support. The major objectives of this network of excellence are to bring these individual efforts together, to integrate new groups, to spread experience to other groups in order to maximise the benefits of collaborative brain banking. Brain and tissue banking at a European scale is of particular importance to study genetic and environmental influences of common diseases, to make possible studies on rare diseases and to guarantee reliable standardised morphological diagnosis of brain diseases all over Europe. The latter is an indispensable prerequisite for good therapeutic studies. BrainNet Europe started as a collaboration of ten brain banks and has now been opened for the integration of new members. Fundamental work has been performed concerning ethical aspects, diagnostic standards, tissue handling and sampling protocols, as well as data storage and exchange using various tools of information
Expected results
1. SHORT -TERM OBJECTIVES AND ACHIEVEMENTS 1) to generate and foster collaboration between different centres undertaking brain banking and associated research activities; 2) to maximise access to a range of tissues from particular diseases, collected from a number of different centres under standard conditions and with well documented clinical histories; 3) to maximise access to sufficient numbers of control cases appropriate to the disease of study; 4) to harmonise protocols for individual disease-directed research; 5) to develop methodologies which would have wide application in brain banking, e.g. optimisation of different methods of freezing tissue; 6) to disseminate current skills in enlisting public support for, and interest in, brain banking as a means of studying brain diseases; 7) to use the Internet for exchange of information,for raising scientific awareness regarding currently available tissue samples, for refinement of current diagnostic criteria,for multi-centre validation of qualitative and quantitative research data, and for networked training sessions;
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Management structure of BNE II
8) to train young researchers in the use and application of human nervous system tissues for research, by means of short-term visits to other centres, training fellowships, and workshops. 2. LONG-TERM OBJECTIVES AND ACHIEVEMENTS 1) to seek new ways to support the neuroscience research community, e.g. blood and DNA collections and the routine inclusion of non-CNS tissue samples in the Bank; 2) to invite other Brain Banks to join the network if it is successful, while being mindful of the need to preserve the viability and worth of the project; 3) to encourage the development of a collaborative ethos among smaller Banks and tissue resources on a national basis; 4) to encourage good practice and reduce duplication between Banks and tissue collections; 5) to ensure that additional nervous system diseases of high morbidity and burden on healthcare resources are addressed within the network; 6) to ensure that high-quality samples are collected from rare diseases and from foetuses in order to encourage and facilitate research in ontogeny and unusual neuropathological material;
7) to devise strategies which lessen the impact of different legislative practices concerning autopsies in different European countries; 8) to consider alliances with pharmaceutical and technology industries; 9) to consider inclusion of data regarding primate and transgenic resources; 10) participation in, and access to, a networked source of disease and control tissues of high quality will both stimulate and facilitate the scientific output from individual centres, which in turn will help to secure ongoing funding for individual Brain Banks.
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Coordinator
Prof. Kretzschmar, Hans Ludwig Maximilians Universitaet Muenchen Institute of Neuropathology and Prion Research Feodor-Lynen-Str. 23 81377 Munich, Germany Phone: + 49 89 2180 78000 Fax: + 49 89 2180 78037 E-mail: Hans-Kretzschmar@inp.med.uni-muenchen.de Project web-site: www.brainnet-europe.org Key words: brain bank, neuroscience, genomics, proteomics
Universit di Bologna Dipartimento di Scienze Neurologiche, Bologna, Italy Department of Neuropathology, National Institute of Psychiatry and Neurology, Budapest, Hungary Human Brain Tissue Bank, Department of Anatomy, Semmelweis University, Budapest, Hungary Department of Neuropathology, Bereich Humanmedizin Georg-August University Goettingen, Germany Department of Psychiatry and Psychotherapy, Saarland University, Germany Department of Neuroinflammation, Imperial College of Science Technology and Medicine, London, United Kingdom Laboratoire danatomie pathologique, Hospices Civils de Lyon, Lyon, France Clinical Neurochemistry Lab, Julius Maximilians University Wrzburg, Germany GABO Gesellschaft fr Ablauforganisation, Informationsverarbeitung und Kommunikationsorganisation mbH & Co. KG, Munich, Germany
Partners
Department of Neuroscience and Neurology, Neuropathology section, University of Kuopio, Finland Pathology (Neuropathology), School of Clinical and Molecular Medicine, University of Edinburgh, United Kingdom Huddinge Brain Bank, Karolinska Institute, Geriatric Department, Neurotec, Stockholm, Sweden Institute of Neurology, University of Vienna, Austria Division of Neuropathology and Neurology 5, Istituto Nazionale Neurologico Carlo Besta, Milan, Italy Institute Neuropathology, Hospital de Bellvitge, Universitat de Barcelona, Spain Laboratoire de Neuropathologie Raymond Escourolle, Institut National de la Sant et de la Recherche Medicale, Paris, France Department of Neuropathology, King`s College London, United Kingdom Netherlands Brain Bank Foundation, Amsterdam,The Netherlands Department of Pathology / School of Medicine, National and Kapodistrian University of Athens, Greece
Acronym: BrainNetEurope II Project number: LSHM-CT-2004-503039 EC contribution: 7 740 000 Instrument: Network of Excellence Duration: 60 months Starting date: 01/07/2004
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AUTISM MOLGEN
Using European and International populations to identify autism susceptibility loci

Summary
The Autism STREP group will pool data from 425 previously ascertained multiplex families and perform a meta-analysis to identify the top 6 susceptibility regions.The top susceptibility regions will then be tested in genetically isolated populations of Finnish and Friesland singleton trios to search for extended haplotypes that may further refine the critical regions. Brain expressed candidate genes in these narrowed regions will be tested for mutations and association with autism. In parallel, previously identified potential candidate genes will be tested for mutations/association in the combined sample of multiplex families.
Expected results
1. Identification of top 6 linkage regions in combined multiplex sampl and analysis of parent of origin and methylation effects in candidate genes 2. Identification of extended haplotypes for the top 6 regions in Finnish and Netherlands singleton trios. 3. Identification of any mutations/aetiological variants in brain expressed candidate genes in top 6 linkage regions. 4. Identification of any mutations/associations in named candidate genes.
Background
Autism spectrum disorders are handicapping, neurodevelopmental diseases of childhood that persist into adult life and which usually arise on the basis of a complex genetic predisposition.The brain basis of autism remains contentious, although post mortem studies provide clear evidence of neuropathology with a prenatal onset. Identifying susceptibility alleles is a key for understanding the molecular and cellular nature of the brain dysfunction and for developing rational preventative and treatment strategies to improve quality of life. Although there has been significant progress towards identifying susceptibility alleles,this has not yet been achieved by research groups working independently.
Aim
1.To perform a meta-analysis of linkage in all multiplex families and search for extended haplotypes in two isolated populations. 2.To test brain expressed candidate genes in 6 regions of linkage for mutation and association with autism. 3.To test named candidate genes for mutations/association with autism in multiplex families. 4.To assess and genotype new multiplex and singleton families.
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Coordinator
Prof.Anthony James Bailey The Chancellor, Masters and Scholars of the University of Oxford University Section of Child and Adolescent Psychiatry Park Hospital for Children Old Road, Headington OX3 7LQ Oxford, United Kingdom Phone: +44 1865 226517 Fax: +44 1865 762358 Anthony.bailey@psych.ox.ac.uk Project web-site: not yet established Key words: Autism, Neurology, genetics, rare disease
Partners
Prof. Patrick Farrar Bolton Kings College London Child Psychiatry & MRC Centre for Social, Developmental & Genetic Psychiatry London, United Kingdom Prof.Ann Simone Le Couteur The University of Newcastle Child and Adolescent Psychiatry/Mental Health School of Clinical Sciences Newcastle upon Tyne, United Kindgom Dr. Lennart Pedersen Center for Autisme Bagsvaerd, Denmark Prof. Marion Leboyer Institut National de la Sant et de la Recherche Mdicale INSERM U513 Creteil, France Prof. Bernadette Roge Universit de Toulouse Le Mirail Centre d'Etudes et de Recherches en Psychopathologie (CERPP) Toulouse, France Prof. Fritz Poustka Johann Wolfgang Goethe-Universittsklinikum Klinik fr Psychiatrie und Psychotherapie des Kindes- und Jugendalters Frankfurt, Germany Prof. John Tsiantis Natinoal and Kapodistrian University of Athens Department of Child Psychiatry,Athens University Medical School,Agia Sofia Children's Hospital Athens, Greece
Prof.Agatino Battaglia Stella Maris Clinical Research Institute for Child & Adolescent Neuropsychiatry Calambrone, Italy Dr. Maretha de Jorge University Medical Center Department of Chile and Adolescent Psychiatry Utrecht,The Netherlands Prof. Rudolf Minderaa Stichting Universitaire en Algement Kinder- en Jeugdpsychiatrie Noord-Nederland Faculty of Medical Sciences, Groningen University Department Child and Adolescent Psychiatry Groningen,The Netherlands Prof. Christopher Gillberg Goteborg University Department of Child and Adolescent Psychiatry Gteborg, Sweden Dr. Irma Jrvel Helsinki University Central Hospital Laboratory of Molecular Genetics Helsinki, Finland Dr.Thomas Bourgeron Institut Pasteur Groupe a 5 ans, Human Genetics and Cognitive Functions Paris, France Prof.Annemarie Poustka Deutsches Krebsforschungszentrum Molecular Genome Analysis Heidelberg, Germany Prof. Elena Maestrini Alma Mater Studiorum - Universit di Bologna Dipartimento di Biologa Evoluzionistica Sperimentale Bologna, Italy
Acronym: Autism Molgen Project number: LSHM-CT-2004-512158 If not, proposal number: 512158 EC contribution: 2 000 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: tbd
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SYNSCAFF
Synaptic scaffolding proteins orchestrating cortical synapse organisation during development

Summary
The development of neural circuitry is a vastly complex process, and the role of many of its components - notably the control of neuronal morphology, the formation of specific synaptic connections as well as the localisation of key synaptic proteins - is still very poorly understood. In this frame the present project aims to reach a more comprehensive understanding of cortical networking during development, in particular of genes and their products governing complex molecular mechanisms driving synaptic structuring and organisation during development of cortical networks and circuitries. This project integrates the information about the role of different candidate genes/proteins in synaptic formation,remodelling and function and it capitalises on results obtained in in vitro systems and translates them to clinical application. The final aim is to identify key steps responsible for defect of development associated to mental retardation.Since intellectual performances are directly related to brain development and plasticity of excitatory synapses and these are generally located in cortical neurons, the project focuses primarily on these structures. The proteins identified as important factors in the development of functional synapses are then studied for their implications in the development of synaptic dysfunctions using different animal genetic models of mental retardation. Thus the project: i) characterises gene products responsible for synapse formation and function ii) assesses the role of mutation/deletion of selected genes in synaptic function in in vitro systems and in intact organisms iii) analyses the impact of mutations of scaffolds in driving mental retardation.
Background
It is still unclear how the complex and finely tuned network of protein-protein interactions defining both the presynaptic cytomatrix and the postsynaptic compartment of cortical synapses are regulated during development. It is well known that development of CNS synapses in vivo follows a stereotyped pattern. Thus, during development - as well as during synaptic activity - a profound rearrangement in synaptic protein composition and distribution occurs. These changes induce functional and morphological modifications allowing a reset of neuron activity in order to better respond to a new environment. Such a modification represents the basis of structural dynamics of synapse, a process that has a crucial role in development of the neuron system. Several of these changes occur at the synaptic,cytoskeletal and scaffold proteins level that represents a large proportion of the entire neuron proteoma. In fact chemical synapses are characterised by electrondense cytomatrices on both sides of the synaptic junction. On the pre-synaptic side dense projection or cytomatrix assembled at the active zone (CAZ) defines the site of neurotransmitter release and it is thought to organise membrane trafficking events underlying the synaptic vesicle cycle. On the post-synaptic side the post-synaptic density (PSD) defines the neurotransmitter reception apparatus and is believed to anchor and cluster neurotransmitter receptors, ion channels, and cell adhesion molecules and to connect them to the
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subsynaptic cytoskeleton and to elements of the postsynaptic signal transduction machinery. In particular the identifications of scaffolding proteins as essential components of CAZ and PSD structure, has revealed new insights into the molecular and assembly mechanisms of the synaptic apparatus. In many cases multiple protein-protein interaction among scaffolding and other synaptic relevant proteins have been described,highlighting their appropriateness in driving the assembly of the synapse during development. Nevertheless,the discrete/distinct mechanism by which these proteins participate in the regulation of synaptic development and function remain largely unknown. Disturbance of dendritic spine shape, synaptic function and organisation of scaffolding proteins and receptor may lead to abnormal development of cortical circuitry. The functional outcome of these disturbances is read as a defect of plasticity of these structures,a defect that may lead ultimately to mental retardation.
Expected results
The development of neural circuitry is a vastly complex process, and the role of many of its components - notably those that control neuronal morphology, formation of specific synaptic connections as well as the localisation of key synaptic proteins - are far from being fully understood, although an alteration of this structure dramatically compromises brain function.This project contributes to expand the knowledge in synapse formation during development not only by identifying key genes involved in this project but also providing a picture of the correct spatial localisation of these proteins in the synaptic space, the latter being fundamental to understand their unique and specific role. Thus specific expected results will be: characterisation of gene products responsible for synapse formation, and function focusing on: the molecular scaffold cytomatrix of cortical synapses, identifying interacting elements with already known components and analysing their function at molecular and cellular level; the molecular scaffold organising the post-synaptic domains and their role in sorting, targeting and function of ionotropic and metabotropic membrane receptors; the intercellular processes dynamically regulating the assembly of synaptic elements and determining the functional properties of the newly formed spines, i.e. phosphorylation processes mediated by different classes of kinases. Evaluation of the role of mutation/deletion of selected genes in synaptic function in in vitro systems and in intact organism. Evaluation of the impact of mutations of scaffolds in driving mental retardation.
Aim
The major goal of the present project is to reach a better understanding of cortical networking during development and in particular of genes and their products governing the complex molecular mechanisms driving synaptic structuring and organisation during development of cortical networks and circuitries. In fact although genomic studies strongly contributed to our knowledge on genes responsible for cortical development (identifying more than 437 gene products in foetal human brain), it is known that the development of neural circuitry is a vastly complex process, and the role of many of its components - notably the control of neuronal morphology, the formation of specific synaptic connections as well as the localisation of key synaptic proteins - is still very poorly understood. This project integrates the information about the role of different candidate genes/proteins in synaptic formation, remodelling and function and it capitalises on results obtained in in vitro systems and translate them to clinical application, with the final aim to identify key steps responsible for defect of development associated to mental retardation. Since intellectual performances are directly related to brain development and plasticity of excitatory synapses and these are generally located in cortical neurons, the project focuses primarily on these structures. Thus, the hypothesis that genes involved in the dynamic organisation of pre- and post-synaptic compartment - studied in detail by the consortium - may be responsible for some aspects of brain dysfunction leading to mental retardation, are tested. The final goal is thus to define the molecular portrait of the cortical synapse during development, the key localisation of gene products within the synaptic structure, which will possibly lead to the definition of key genes involved in mental retardation.
SYNSCAFF generates novel information on the mechanisms underlying synapse formation during development with reflection on the causes of mental retardation.This is a major contribution, as the biological mechanisms underlying mental retardation remain obscure. This novel information is also used to devise new innovative diagnostic tools in order to allow for an early diagnosis and possibly treatment of these diseases. In addition, in a larger scale, most of proteins responsible for the structural organisation of the synapse are involved not only in developmental disorders but also in some aspects of synaptic loss in neurodegenerative disorders. Thus, results obtained in the consortium have a larger impact, being applicable to several fields. SYNSCAFF provides new molecular targets for treatment. This secures transfer of results generated to compounds that would have in the future an impact on the early diagnosis of mental disorders.
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Coordinator
Di Luca, Monica University of Milan Department of Pharmacological Sciences via Balzaretti, 9 20133 Milan, Italy Phone: + 39 02 5031 8374 Fax: + 39 02 2048 8250 E-mail: monica.diluca@unimi.it Project web-site: www.synscaff.org Key words: cortical development, scaffolding proteins, presynaptic cytomatrix, postsynaptic density, glutamate receptors
Muller, Dominique Faculty of Medicine, Pharmacology (Department APSIC) Centre Mdical Universitaire Switzerland Gundelfinger, Eckart D Leibniz Institut fr Neurobiologie Abteilung fr Neurochemie und Molekularbiologie Magdeburg, Germany Sala, Carlo Consiglio Nazionale delle Ricerche Institute of Neuroscience Milan, Italy Calabresi, Paolo NeurosciTorVerRome - Dipartimento di Neuroscienze Universit di Roma Tor Vergata Rome, Italy Blahos, Jaroslav Institute of Experimental Medicine Czech Academy of Science Prague, Czech Republic Jebavy, Lukas BioTest s.r.o. Konarovice, Czech Republic Finocchiaro, Carla CF Consulting SrL Milan, Italy
Partners
Mulle, Christophe Univ Bordeaux 2 - CNRS UMR 5091 Inst Francois Magendie Bordeaux, France Fagni, Laurent Laboratoire de Gnomique Fonctionnelle UPR CNRS 2580 Montpelllier, France Debanne, Dominique Institut National de la Sant Et de la Recherche Mdicale INSERM U464 Ionic Channels Marseille, France Prof. Lscher, Christian Departments de Pharmacologie et Physiologie Service de Neurologie Clinic of Neurology (Department NEUCLID), Lab for Addiction Science Switzerland
Acronym: SYNSCAFF Project number: LSHM-CT-2004-511995 EC contribution: 1 900 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/01/2005
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EUROHEAD
Migraine genes and neurobiological pathways

Summary
Migraine is a common chronic pain syndrome for which effective and well-tolerated prophylactic agents are much needed. Increased knowledge of migraine pathophysiology is a prerequisite. In EUROHEAD the genetic and neurobiological basis of the initiation of migraine attacks, the aura, and migraine pain will be investigated. A second focus of the EUROHEAD Consortium is to promote and disseminate knowledge on clinical and neurobiological science of migraine and other primary headache syndromes. patients and experimental animal models. In addition, the EUROHEAD Consortium wants to promote and disseminate the existing and newly acquired knowledge of the underlying clinical and neurobiological science of migraine syndromes among clinicians, scientists, patients and general public worldwide.
Expected results
In the EUROHEAD project, a Centre of Excellence has been established in which many of the expert groups on primary headaches are involved. Among the expected results are the identification and validation of (new) loci and gene variants for migraine, the analysis of functional consequences of migraineassociated gene variants and mutations in cellular and animal models, the correlation of genotypic data with migraine-endophenotypes, an evaluation of headache science in Europe, and importantly further promotion and dissemination of knowledge and awareness in the community on this serious disorder.
Background
Migraine is characterised by recurrent attacks (lasting 1-3 days) of disabling headache,associated symptoms and,in one-third of patients, neurological aura symptoms.Over 12% (two-thirds of which is female) of the general population have migraine attacks regularly (median 18/year).WHO rates migraine in the highest class of most disabling chronic disorders. Migraine-related annual costs in the EU amount to 10 billion.Acute attack treatments are satisfactory in less than half of patients. Effective and well-tolerated prophylactic migraine agents are needed. Genetic factors are involved in the mechanisms for the attack, aura and pain. Rare familial and common complex types of migraine might share common genes and pathways. Unravelling the genetic and neurobiological basis of migraine by identifying and validating migraine genes and studying their functional involvement with various techniques in patients and experimental models will increase our knowledge and awareness of migraine as a serious neurobiological disorder.
EUROHEAD research will be important for a better understanding of the pathophysiology of migraine and future drug development.
Aim
EUROHEAD aims to unravel the genetic and neurobiological basis of the migraine. To this extent, EUROHEAD will identify and validate migraine genes and study their functional involvement with state-of-the-art techniques in
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Coordinator
Prof. Ferrari, Michel Leiden University Medical Centre Department of Neurology Albinusdreef 2, NL 2300 RC Leiden,The Netherlands Phone: +31 71 526 2895 Fax: +31 71 527 8253 E-mail: M.D.Ferrari@lumc.nl Project web-site: www.eurohead.org Key words: headache, migraine, pain, genetics, neurobiology, man, transgenic mouse models, response, treatment
Dr. Casari, Giorgio Fondazione Centro San Raffaele del Monte Tabor Human Molecular Genetics Unit Department of Neuroscience Milan, Italy Prof. Diener, Hans-Christoph Universitt Duisburg Essen Department of Neurology Essen, Germany Prof. Olesen, Jes Glostrup University Hospital Danish Headache Center Dept. Neurology Copenhagen, Denmark Prof. Schoenen, Jean University of Lige Department of Neuroanatomy & Neurobiology Faculty of Medicine Headache Research Unit Lige, Belgium Prof. Nappi, Giuseppe IRCCS Neurological Institute "Casimiro Mondino" Pavia, Italy
Partners
Prof. Palotie,Aarno University of Helsinki Finnish Genome Center Helsinki, Finland Prof. Goadsby, Peter Institute of Neurology University College London Headache Group London, United Kingdom Prof. Pietrobon, Daniela Universit degli Studi di Padova Dipartimento di Scienze Biomediche Sperimentali Padova, Italy
Acronym: EUROHEAD Project number: LSHM-CT-2004-504837 EC contribution: 3 200 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/05/2004
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SPASTICMODELS
Genetic models of chronic neuronal degeneration causing hereditary spastic paraplegia

Summary
Neurodegenerative disorders,a heterogeneous group of chronic progressive diseases, are among the most puzzling and devastating diseases in medicine. Indeed they are characterised by onset in adult life, distinct clinical phenotypes,and specific degeneration of subsets of neurons and axons. Hereditary spastic paraplegia (HSP) is a disorder that results in progressive weakness and spasticity of the lower limbs affecting approximately 1 in 10 000 individuals. Heterogeneity characterises HSP in both clinical and genetic aspects.Little is known about the pathogenesis of HSP and consequently no specific treatment is available to prevent, cure or delay progression of symptoms of HSP. Electrophysiological and pathological findings point to the corticospinal tracts,dorsal columns and the spinocerebellar fibres as the structures primarily affected by HSP. Two main pathogenetic hypotheses for the neurodegeneration seen in HSP, as well as other neurodegenerative conditions, have recently emerged, suggesting that impaired mitochondrial function and/or defective subcellular transportation mechanics play a crucial role.In fact, HSP-causing mutations have been found in gene products involved in mitochondrial function, such as paraplegin and HSP60, and axonal trafficking, such as kinesin and, possibly, spastin and spartin. This consortium of European groups intends to provide a multi-faceted comprehensive approach to study the pathogenesis of HSP with a particular emphasis on the role of mitochondrial dysfunction and impaired axonal transport, through the production and extensive characterisation of seven novel mouse models for this disease,in parallel with the recently developed paraplegin null mutant. The proposed strategy is a highly integrated effort to study the function of several HSP genes,with the final goal of identifying common mechanisms leading to axonal degeneration, which will be potential targets of a therapeutic intervention in the long term. Semithin section of the spinal cord of a 8 month-old paraplegin-deficient mouse showing axonal swelling.
Background
Hereditary spastic paraplegia (HSP) consists of a heterogeneous group of neurodegenerative diseases characterised by progressive lower-limb weakness and spasticity and subtle impairment of the vibratory sense. Age of onset is quite variable, generally between 10 and 40 years old. HSP has been classified traditionally as pure or complicated, depending on whether spastic paraplegia is the only symptom or whether it is found in association with other neurological abnormalities, such as optic neuropathy, retinopathy, extrapyramidal symptoms, dementia, ataxia, mental retardation and deafness. Neuropathological analyses of tissues from a small number of individuals with pure HSP have shown axonal degeneration involving the more distal portions of the longest motor and sensory axons of the central nervous system (i.e. the crossed and uncrossed corticospinal tracts, the fasciculum gracilis and the spinocerebellar tracts).A specific pattern of degeneration is seen in HSP, during which the cell bodies remain largely intact while the degeneration is principally limited to the cell axon and may be a dying back axonopathy, beginning distally and proceeding towards the cell body. A more precise classification of HSP forms therefore originates from the inheritance pattern,which may be autosomal dominant,autosomal recessive or X-linked recessive.So far,21 loci have been mapped (listed SPG1 to SPG21);however,causative mutations have been found in nine genes only. Mutations in the cell adhesion module L1, L1CAM (SPG1) and in the proteolipid protein, PLP (SPG2) cause X-linked forms of HSP characterised by defects in the development of the corticospinal tract and in axonal-glial interactions,respectively.Little is known about
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known autosomal HSP genes encoding spastin (SPG4), paraplegin (SPG7),atlastin (SPG6),spartin (SPG20),aspardin (SPG21),while Hsp60 is a well-characterised shock-response protein (SPG13) and the neural specific kinesin gene KIF5A (SPG10) is a member of the kinesin superfamily of molecular motors that transport cargoes along microtubules. Atlastin is a novel GTPase that has sequence homology to members of the dynamin family of large GTPases, particularly guanylate binding protein-1. Spartin is responsible for Troyer Syndrome, an autosomal recessive HSP, and is homologous to proteins involved in endosome morphology and protein trafficking of late endosomal component. Aspardin is responsible for Mast syndrome (a spastic paraplegia, autosomal recessive with dementia). Both spastin and paraplegin are AAA proteins, ATPases associated with different cellular activities. Members of this superfamily of ATPases exert chaperon-like activities and mediate assembly and disassembly of macromolecular structures involved in different cellular processes. Paraplegin resembled a family of mitochondrial metalloproteases well-characterised in yeast and was shown to localise in the mitochondrion. Mutations in paraplegin cause neurodegeneration in an autosomal recessive form of HSP, but the pathogenetic mechanism of this disorder, in particular the role of mitochondria, is presently not understood. Observations of members of this Consortium (Partners 1 and 4) show that paraplegin and the homologous protein AFG3L2 constitute the m-AAA protease complex. Mitochondria of HSP patient (SPG7) have indeed a functional deficit that could result from impaired protein quality control, causing an accumulation of misfolded proteins within the mitochondrial matrix. An additional mitochondrial protein, Hsp60, has been found mutated in a form of HSP. Hsp60 is a representative of the type I chaperonin subfamily of molecular chaperones that are involved in folding of bacterial, mitochondrial and chloroplast proteins. Type I chaperonins are highly conserved throughout evolution and play an important role in quality control of proteins, which seems to be a preferential mitochondrial target for SPG13 and SPG7. Differently, some evidence from transfection experiments show that spastin interacts with microtubules and seems to modulate microtubule dynamics, an essential attainment for maintenance of long axons,beside a still unclear possible role at nuclear level. Only little is known, however, about the function of this protein and its role in the pathology of HSP. The specificity of the axonal damage in HSP apparently contrasts with the wide distribution and range of functions carried out by the few gene products known to cause the clinical phenotypes. However, we think to envisage two possible pathogenetic mechanisms. The mitochondrial way seems to affect neuronal metabolism, in particular at the axon extremity, by reducing the available energy. On the other hand, the cellular trafficking impairment would limit the turnover of fresh molecules and organelles to and from the periphery of neurons. Both
mechanisms would result in a dying-back effect, typical of this late progressive neurodegeneration. A possible unifying alternative mechanism can be hypothesised: impaired mitochondrial function generates huge aberrant mitochondria, which engulf the peripheral cellular trafficking.
Aim
Current therapies provide only symptomatic relief; none significantly alter the course of disease.Therefore, there exists a major medical need that demands the development of new and more informed therapeutics for the efficacious treatment of neurodegenerative diseases.While many diseases of the motor neurons have no known genetic component, recent investigations have begun to identify the causative genes for some familial forms. In turn, this leads to the possibility of transgenic animal models of human disease, which in previous studies have substantially contributed to the identification of many promising new therapies. A major limitation to the study of neurodegenerative disease is that the affected tissues are not accessible until after death, hampering studies of the early stages and the progression of the pathological features. Animal models where the genes mutated in human HSP are modified are an important tool to overcome this obstacle.
Expected results
This consortium of European groups intends to provide a multifaceted approach for the study of the HSPs and these mechanisms. Although the molecular basis has been unravelled for several forms of HSP in the last few years, the mechanisms resulting in axonal degeneration in this disease are still largely unknown. However animal models offer an important tool to overcome this obstacle. The objectives of this work package are: 1) the generation of mouse models for different forms of HSP; 2) the phenotypic characterisation of these models according to common, standardised protocols.
Electron micrograph of the spinal cord of a12-month-old paraplegin-deficient mice showing segmental swelling of a longitudinally cut axon. Filamentous aggregates and and degenerating mitochondria accumulate in the axoplasm.
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A critical component of the proposed project is the development and characterisation of a number of mouse models of hereditary spastic paraplegia, which include: spastin (SPG4), paraplegin (SPG7), Hsp60 (SPG13), spartin (SPG20), Afg3l1 and Afg3l2 and prohibitin. This comprehensive range of models affords this project an invaluable resource for the study of disorders of the motor neuron, in particular the hereditary spastic paraplegias. We will use this resource, in parallel with a range of cell models and other studies, to examine two hypotheses for motor neuron degeneration: defective mitochondrial function, and abnormal subcellular transportation mechanics.
Coordinator
Dr Casari, Georgio San Raffaele Scientific Institute DiBit Via Olgetttina, 58 20132 Milan, Italy Phone: + 39 02 2643 3502 Fax: + 39 02 2643 4767 E-mail: casari.giorgio@hsr.it Project web-site: http://www.spasticmodels.org/ (under construction). Key words: hereditary spastic paraplegia, paraplegin, spastin, spartin, HSP60, motoneuron, mouse models.
Partners
Dr Rugarli, Elena TIGEM Naples, Italy Prof. Langer,Thomas Universitt zu Kln Institut fr Genetik, Cologne, Germany Prof. Bross, Peter Aarhus University Hospital Skejby Sygehus Brendstrupgaardsvej rhus N, Denmark Dr Crosby, Andrew St. Georges Hospital Medical School London, United Kingdom Prof. Deufel,Thomas Instituts fr Klinische Chemie und Laboratoriumsdiagnostik Universittsklinikum Jena Jena, Germany
Acronym: SPASTICMODELS Project number: LSHM-CT-2003-503382 EC contribution: 1 900 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/01/2004
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NCL-models
Dissecting neuronal degeneration: Neuronal ceroid lipofuscinoses from genes to function

Summary
The aim of the NCL-models project is to reveal pathogenetic mechanisms in neuronal ceroid lipofuscinoses.Our goal is to carefully characterise the individual NCL proteins to further understanding of their normal roles and the molecular mechanisms by which loss of their function leads to neurodegeneration. The data we obtain will also have significant implications for other disorders,providing insights into the cellular processes that influence neuronal death and ageing. The project uses a multidisciplinary approach, in which a key element is the generation of novel models for NCL.These models, including cell, yeast, nematode and mouse models will then be used to study the pathogenetic mechanisms of NCLs by a variety of techniques including molecular genetics, cell biology, mRNA and protein expression profiling, proteomics, and morphological approaches.The combination of top-level European NCL scientists will facilitate the integration of research capacities across Europe,increasing coherence and providing critical mass of investigators. The integrated multidisciplinary research enables direct interactions between technology and biology and will provide the knowledge base essential for the rational design of therapeutic interventions. 3) to further characterise the neuronal phenotype of the five existing mouse models and to develop one novel mouse model of NCL; 4) to define the mechanisms and selectivity of neurodegeneration in the model organisms; 5) to develop and use bioinformatic tools for efficient analysis of the metabolic pathways involved in neuronal degeneration; 6) to organise effective European research training in the functional genomics of neurodegeneration; 7) to integrate the complex data arising from different model systems in order to understand the cellular pathogenesis unique to each NCL or in common between the NCLs thereby providing the knowledge base for future drug development. Additionally, actions to raise public participation and awareness will be taken.
Expected results
The present project will significantly add to our knowledge of the function of the NCL proteins, the mechanisms of neurodegeneration and the disturbed metabolic pathways underlying each form of NCL. This project will lead to better understanding of the maintenance of the nervous system,and will provide the knowledge base for designing therapy, and essential tools for evaluating subsequent therapeutic approaches. Research training is an extremely important part of this multidisciplinary programme and one central task is to organise and monitor the research training of young scientists devoted to functional genomics and neurobiology. Exchange of these junior investigators between laboratories will help to provide them a thorough training in different techniques. It is also expected that exchange of young scientists between laboratories of the collaborative network will facilitate the achievement of the research goals of the NCL-models project.
Background
The neuronal ceroid-lipofuscinoses (NCLs) are collectively the most common inherited progressive encephalopathy of childhood.Each form of NCL is characterised by the progressive death of cortical neurons and these rare diseases provide an excellent model to define the molecular events that result in neurodegeneration. Using genomic approaches we have identified six genes mutated in different forms of NCL: PPT1, CLN3, CLN5, CLN6, CLN8, and cathepsin D. Deficiencies in these proteins result in a group of fatal disorders with clinical presentation that ranges from infantile lethality to later onset and more protracted forms. Despite the identification of these proteins, the underlying pathogenetic mechanisms remain unclear.
The ultimate impact of the proposal is in providing the basis for therapeutic approaches for these progressive, fatal neurodegenerative disorders of childhood.The entire NCL-models network aims at improving the health of NCL patients and quality of life for families affected by this major paediatric neurodegenerative disease.The economic development and impact produced by these research achievements will be assessed during the course of the project. Once these research data influence, initiate or enhance therapeutic activities and form the basis of clinical trials, economic benefits will be expected not only for the manufacturers of eventual therapeutic regimens but also via lowering disease costs incurred by NCL patients and their families.
Aim
The project has been divided into seven specific objectives: 1) to analyse the localisation, transport and molecular interactions of the individual NCL proteins in neuronal and non-neuronal cell models; 2) to generate and analyse yeast and nematode models for different forms of NCL;
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Coordinator
Dr Jalanko, Anu National Public Health Institute, Department of Molecular Medicine, Biomedicum Helsinki P.O. Box 104 00251 Helsinki, Finland Phone: + 358 9 4744 8392 Fax: + 358 9 4744 8480 E-mail:Anu.Jalanko@ktl.fi Project web-site: www.nclmodels.org Key words: neurological disorder, neurodegeneration, neuronal death
Dr Lehesjoki, Anna-Elina Neuroscience Center Department of Medical Genetics and Folkhlsan Institute of Genetics Biomedicum Helsinki University of Helsinki, Finland Dr Tyynel, Jaana Institute of Biomedicine/biochemistry University of Helsinki, Finland Dr Cooper, Jon D Pediatric Storage Disorders Lab Department of Neuroscience Institute of Psychiatry King's College London London, United Kingdom Dr Taschner, Peter Department of Human Genetics Sylvius Laboratories Leiden,The Netherlands Dr Braulke,Thomas University Hospital Hamburg-Eppendorf Hamburg, Germany
Partners
Dr Peltonen-Palotie, Leena Department of Medical Genetics University of Helsinki and Department of Molecular Medicine National Public Health Institute Biomedicum Helsinki, Finland Dr Mole, Sara E Department of Paediatrics and Child Health Royal Free and University College Medical School University College London, Bloomsbury Campus London, United Kingdom Dr Mitchison, Hannah Senior Lecturer in Molecular Genetics Department of Paediatrics and Child Health Royal Free and University College Medical School University College London, London, United Kingdom
Acronym: NCL-models Project number: LSHM-CT-2003-503051 EC contribution: 2 000 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date:01/01/2004
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NEUROKCNQPATHIES
Cell biology of rare monogenic neurological KCNQ disorders

Summary
Mutations in three KCNQ genes are associated with rare monogenic neurological disorders prompting us to study the cell biology underlying these disorders, and to identify the processes that control KCNQ channel function. The biochemical and biophysical affects of these mutations in the channels,their modulation by second messengers,and the physiological significance of protein-protein interactions will be addressed. Because some mutations in the KCNQ loci do not appear to lie in the coding region, we will study the transcriptional control of these genes. Furthermore, mouse models will be produced to gain a more precise idea of the pathology of these diseases. Finally, the molecular basis for drug specificity will be analysed to define the mode of action as well as to identify and characterise new drugs that affect the function of these channels. The M-current is a target of acetylcholine and it is thought to play a role in learning and memory, and in epilepsy. Indeed, KCNQ channel modulators may have therapeutic potential in the treatment of epilepsy, neuropathic pain and neurodegeneration. For this reason, we must understand more precisely how these modulators of KCNQ channels work to fully explore this therapeutic potential. Finally, KCNQ channelopathies provide an example of the importance of gene dosage in inherited diseases. Thus, mutations that only moderately reduce the expression of a KCNQ gene could cause neurological disorders and mutations responsible for producing a disease may lie outside the coding region.
Aim
The principal aim of this project is to determine the role of Mchannels in neuronal and non-neuronal physiology, and to understand the cellular basis of rare neurological syndromes associated with KCNQ channel dysfunction. The function and potential role of KCNQ5 in disease will also be assessed in mutant mice. Conditional KCNQ knock-out mice will aid in further elucidating the involvement of the M-current in neuronal plasticity and we shall also analyse the role of KCNQ channels in human deafness in greater depth. We aim to understand the processes underlying cellular targeting and trafficking of the channels and to identify targeting signals within the channel.We will study the role of associated proteins and second messenger systems in regulating M-channel function as well as the interactions between such elements, and we will identify and study the role of the KCNQ ligands in channel function. We also plan to study how the expression of these genes is regulated. Finally, the role of Mchannels in neuropathic pain processing warrants deeper investigation and we plan to identify the molecular determinants for the pharmaceutical regulation of these channels, which may help in developing more selective drugs
Background
Of the rare monogenic neurological disorders caused by mutations in KCNQ potassium channels, neonatal convulsions (BFNC), a rare autosomal-dominant disorder, are caused by mutations in KCNQ2 and KCNQ3, whereas in KCNQ4 they cause progressive hearing loss.These genes are responsible for the M-current and KCNQ4 may contribute to the short electrical time constants needed in neurons of the auditory pathway. Since KCNQ5 can also contribute to this current, it too may provoke neurological disorders. The intracellular C-terminal domain of KCNQ mediates interactions with other subunits and proteins. This region is also important for efficient surface expression selective retention, endocytosis and intracellular trafficking, as well as the subcellular localisation of KCNQ channels. However, although proteins that interact with KCNQ subunits have been identified, the signals controlling these processes remain unknown. Similarly, the regulation of the M-current by neurotransmitters is poorly understood and the intracellular second messengers involved remain elusive. Nevertheless, information is available regarding the influence of phospholipase C (PLC), PKC activation, the release of internal calcium, PIP2 and CaM binding on the function of Mchannels.To help us clarify the mechanisms by which the cell biology of these channels is controlled and how it may be affected in human disease, it is clear that we must study the relationships between these regulatory proteins.
Expected results
We expect to gain a much better understanding of the cell biology of these channels and the way in which disease-causing mutations affect these processes. Furthermore, light will be shed on how the behaviour of these channels is modulated by associated proteins, neurotransmitters and second messenger systems, as well as the interactions that occur between these elements. We expect to obtain important insights into the role of KCNQ channels in different human conditions, creating the basis for novel therapies.
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This aspect will be enhanced by augmenting our understanding of the action of drugs that alter the activity of these channels. Finally, we hope to advance both our understanding of the transcriptional control of the genes encoding these proteins.
Coordinator
Dr Villarroel, Alvaro Consejo Superior de Investigaciones Cientficas Unidad de Biofisica CSIC-UPV/EHU Universidad del Pas Vasco Barrio Sarriena S/N 48940 Leioa (Bilbao), Spain. Phone: + 34 94 601 3225 Fax number: + 34 94 601 3360 E-mail: gbxvimua@lg.ehu.es Project web-site: www.KCNQ.com Key words: neurobiology, cell biology, rare diseases, monogenic, ion channels, mouse models, KCNQ, Kv7, potassium channels, structure/function, gene expression, protein interactions, cell physiology, electrophysiology
The potential applications that might arise from this project involve the possible therapeutic benefits of treating the diseases that arise due to mutations in these genes as well as in neuropathic pain. Furthermore, it is likely that the insights into the way that these channels are modulated will also be applicable to other diseases caused by similar proteins, within and outside the nervous system, as well as to diseases involving other types of proteins.
Partners
Centre for Molecular Neurobiology, Hamburg University, Germany Department of Physiology, University College London, United Kingdom Department of Physiology, Institute of Basal Medical Sciences, Medical Faculty, University of Oslo, Norway NeuroSearch A/S, Ballerup, Denmark Unit de Gntique des Dficits Sensoriels, INSERM U587, Institut Pasteur, France. Department of Neuroscience, Section of Pharmacology, University of Naples Federico II, Italy School of Biochemistry & Molecular Biology, University of Leeds, United Kingdom.
Acronym: NEUROKCNQPATHIES Project number: LSHM-CT-2004-503038 EC contribution: 1 900 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/04/2004
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X-ALD
X-linked Adrenoleukodystrophy (X-ALD): pathogenesis, animal models and therapy

Summary
Our ultimate goal is to develop new therapies for X-linked adrenoleukodystrophy (X-ALD), the most frequent inherited monogenic demyelinating disease of the central nervous system (1:18,000). XALD is characterised by extensive phenotypic variability, which is not correlated to ALD genotype, and leads to death in boys due to cerebral demyelination and to motor disability in adults due to spinal cord degeneration. Allogenic bone marrow transplantation, proven to be beneficial in X-ALD, can be applied only to a limited number of X-ALD patients.Thus, there is no treatment for the majority of patients, in particular those with the severe cerebral form of X-ALD and adults with adrenomyeloneuropathy (AMN). Understanding of the pathogenesis is necessary for the development of novel therapeutic strategies.The still unresolved transporter function of the ALD protein will be studied in reconstituted liposomes.To get further insight into the pathogenesis of X-ALD, we aim to identify genes and proteins that are differentially regulated in the target tissues of patients with cerebral ALD and AMN using Affymetrix analysis of differential mRNA expression and a proteomics approach based on MALDI-TOF mass spectrometry. Additional approaches such as mapping of quantitative trait loci will be applied to identify modifier genes that may contribute to the phenotypic variability of X-ALD.We will generate new mouse models that represent a wider phenotypic spectrum of the disease for a more efficient evaluation of therapeutic strategies. Furthermore, we will evaluate four promising new therapy strategies: ALD gene transfer into haematopoietic stem cells, into mesenchymal stem cells, and by direct injection of viral vectors, and pharmacological induction of a related gene as a substitute for the deficient ALD gene. Only the joint effort of the highly qualified partners of this proposal will allow achieving our ambitious aims. biochemically characterised by the accumulation of fatty acids with more than 22 carbon atoms (very-long-chain fatty acids;VLCFA); but the role of VLCFA accumulation in the pathophysiology of the disease remains unknown.The gene affected in X-ALD codes for a protein that is probably involved in the transport of VLCFA into a specific intracellular organelle, called the peroxisome.The ALD protein is an ABC (ATP-binding-cassette) half-transporter, which forms either homo- or heterodimers with two other homologous peroxisomal ABC half-transporters,the ALD-related protein and PMP70.Like many other ABC transporters, the ALD protein binds and hydrolyses ATP to become functional. VLCFA are considered good candidate substrates for transport across the peroxisomal membrane by the ALD protein,but proof of such transport has yet to be demonstrated. In addition,different combinations of heterodimers may have different substrate specificity. Although being a monogenic disorder, X-ALD shows a wide phenotypic variation even within families. There is no correlation between the phenotype and the type of ALD gene mutation or the levels of VLCFA in fibroblasts or plasma of X-ALD patients. This phenotypic variability ranges from severe cerebral forms that lead to death in 5 to12-year-old boys to mild paraparesis (adrenomyeloneuropathy, AMN) in adults at 25-50 years of age. The lack of any genetic or biochemical tools to predict the phenotype of X-ALD hinders the development of preventive or therapeutic approaches. Among the neurometabolic diseases, X-ALD is unique by the occurrence of a striking brain inflammatory response that resembles, but is distinct from, that observed in multiple sclerosis. This immunological response is the main neuropathological factor that seems to differentiate the severe cerebral forms of X-ALD from AMN. There are some speculations in the literature about how this inflammatory response may lead to the death of oligodendrocytes, but its trigger and mechanism are unknown. Since X-ALD is considered a genetic disease with loss-of-function and in the absence of data suggesting that VLCFA are metabolised differently in humans and in rodents, it seemed probable that complete inactivation of the Ald gene in mice would mimic the clinical symptoms observed in XALD patients. The Ald-deficient mice develop a neuropathological phenotype late in life that resembles AMN, but no cerebral demyelination.It is hypothesised that the expression of modifier genes and/or epigenetic factors contributes to the susceptibility or resistance to develop cerebral demyelination both in X-ALD patients and Ald-deficient mice.The only therapeutic approach proven to be beneficial in X-ALD is allogenic bone marrow transplantation (BMT). BMT can reverse or stabilise cerebral demyelination when the procedure is performed in boys at an early stage. However, this procedure is associated with a significant mortality risk (10-25%) and can only be offered to a limited number of X-ALD patients.Thus,there is no treatment for the majority of X-ALD patients,in particular those with the severe cerebral form of X-ALD or adults with AMN.
Background
X-ALD is the most common (1:18 000) genetic disorder affecting the myelin within the central nervous system (CNS). It affects boys (between 5-12 years), adult males (20-50 years), and women (> 40 years).All forms of X-ALD are characterised by severe neurological abnormalities frequently resulting in early death. X-ALD is
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Aim
a) to identify the natural substrates for the ALD protein and other related peroxisomal ABC half- transporters (ALD-related protein and PMP70) whose overexpression, at least partially, overcomes the biochemical defect observed in X-ALD cells; b) to resolve the role of VLCFA in the pathogenesis of X-ALD; c) to get insight into the pathogenesis of X-ALD,we aim to identify genes and proteins that are differentially regulated in the brain of patients with childhood cerebral ALD and AMN; d) identification of the modifier genes that may contribute to the phenotypic variability of X-ALD; e) to characterise in detail the neurodegenerative features of the existing mouse models of X-ALD and to generate new models that represent a wider phenotypic spectrum of the disease; f) to establish a new generation of lentiviral and AAV vectors for gene therapy and to test the efficacy of gene therapy approaches in mouse models aiming at targeting the ALD gene ex vivo in haematopoietic stem cells and in vivo directly to oligodendrocytes; g) to evaluate the ability of autologous mesenchymal stem cells as a potential treatment for presymptomatic and adult X-ALD patients; h) to identify drugs that can stimulate the expression of the ALD-related gene.
Coordinator
Prof. Berger, Johannes Medical University of Vienna Center for Brain Research Division of Neuroimmunology Spitalgasse 4 1090 Vienna, Austria Phone: + 43 1 4277 62812 Fax: + 43 1 4277 9628 E-mail: johannes.berger@meduniwien.ac.at Key words: degenerative diseases, gene therapy, genomics
Partners
Prof. Aubourg, Patrick Institut National de la Sant et de la Recherche Medicale INSERM U561 Service Pdiatrie C Hopital Saint Vincent de Paul Paris, France Dr Pujol,Aurora Institut de Recerca Oncologica (IRO) Centre de Genetica Medica i Molecular (CGMM) Hospitalet de Llobregat Llobregat, Spain Prof. Nave, Klaus-Armin Max Planck-Gesellschaft zur Frderung der Wissenschaft e.V. Department of Neurogenetics Max Plank Institute for Experimental Medicine Gttingen, Germany Prof.Wanders, Ron J A Academic Medical Center University Hospital Amsterdam Department of Pediatrics Laboratory for Genetic Metabolic Diseases, Amsterdam,The Netherlands Dr. Geigle, Peter CELLMED AG Alzenau, Germany
Potential applications and expected results

Prediction of the phenotype will allow the establishment of a preventive and phenotype-adapted treatment for all X-ALD patients identified at birth by systematic screening. X-ALD patients already have increased VLCFA levels at birth, which would enable neonatal screening. Furthermore, clarification of the pathogenesis of X-ALD and the development of new models of X-ALD will allow new therapeutic strategies to be developed and the efficacy of the current envisaged therapeutic approaches to be tested. Preliminary results obtained with ALD gene transfer in X-ALD CD34+ cells and with the pharmacological up-regulation of the Aldr gene in Ald-deficient mice suggest that these studies will lead to phase I/II clinical trials in X-ALD patients.
Acronym: X-ALD Project number: LSHM-CT-2004-502987 EC contribution: 1 800 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/04/2004
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PainGenes
Heritability of chronic neuropathic pain

Summary
Chronic pain undermines the health and welfare of millions of EU citizens and carries enormous financial costs. Individual variability in the burden of pain has traditionally been attributed to psychosocial factors. However, new data indicate that there is an important heritable predisposition to pain, particularly to the development of chronic pain after neural injury (neuropathic pain). Pain susceptibility genes are intrinsically hard to detect in human lineages and populations.This STREP adopts the alternative approach of exploiting new rodent models of neuropathy to uncover pain susceptibility loci and associated neurobiological processes, using inbred mouse strains that show high versus low pain phenotypes. Linkage analysis and positional cloning, together with expression arrays and a variety of electrophysiological and neurochemical methods applied to primary sensory neurons, will be used to identify the biological causes of contrasting pain phenotype. The strategy is to identify genetic and cellular variables that co-vary with pain phenotypes across strains. With mouse candidate genes in hand, identification of the human orthologs is feasible.We stress that our project does not aim to find genes that affect susceptibility to specific disease entities that may be painful. Rather, we focus on genes and processes that determine the amount of pain felt by an individual in the presence of a specific disease Different strains of inbred mice show dramatic, heritable, differences in pain sensitivity. A? Response of 11 mouse trains tested in the neuroma pain model. B.The same strains tested for neuropathic tactile hypersensitivity on the hindpaw. Analysis of across strain correlations and differences can illuminate pain genetics. Results will provide essential background for the development of novel prognostic,diagnostic and treatment options for chronic pain sufferers, with major benefits also for their families, employers and European economies. state or degree of tissue injury. That is, we will investigate pain susceptibility genes rather than disease susceptibility genes. Such genes, and the neural processes with which they are associated, are expected to affect pain intensity irrespective of the proximate cause of the neural damage: trauma, surgery, neoplasm, infection or disease.
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Coordinator
Devor, Marshall Hebrew University of Jerusalem Department of Cell and Animal Biology Institute of Life Sciences, Jerusalem 91904, Israel E-mail: marshlu@vms.huji.ac.il Key words: chronic pain, gene, microarray, nociception, neuropathic pain, neuropathy, pain, pain susceptibility
Fried, Kaj Karolinska Institutet Center for Oral Biology, Novum Karolinska Institutet, Huddinge, Sweden Reeh, Peter University of Erlangen-Nuremberg Institute of Physiology and Experimental Pathophysiology Erlangen, Germany Peth, Gabor University of Pecs Department of Pharmacology and Pharmacotherapy Faculty of Medicine, Pecs, Hungary Michaelis, Martin Aventis Pharma Deutschland GmbH Frankfurt/Main, Germany
Partners
JDarvasi, Ariel Hebrew University of Jerusalem Department of Ecology, Systematics and Evolution (ESE) Institute of Life Sciences Jerusalem, Israel Yakir, Benjamin Hebrew University of Jerusalem Department of Statistics Jerusalem, Israel Tal, Michael Hebrew University-Hadassah Jerusalem Israel Department of Anatomy and Cell Biology Schools of Medicine and Dentistry Ein Kerem, Jerusalem Wiesenfeld-Hallin, Zsuzsanna Karolinska Institutet Department of Laboratory Medicine Division of Clinical Neurophysiology Huddinge University Hospital Stockholm, Sweden
Acronym: PainGenes Project number: LSHM-CT-2004-502800 EC contribution: 1 600 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/05/2004
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GRIPANNT
Glutamate receptor interacting proteins as novel neuroprotective targets

Summary
Excitotoxicity contributes significantly to neuronal cell death in a number of neurological conditions including stroke, head trauma, and Huntingtons disease.The recent discovery of the proteins that anchor and interact with glutamate receptors opens a new strategical approach to cytoprotective therapy. The present project aims at exploiting this conceptual advance to provide a platform for cytoprotective therapies that do not interfere unduly with synaptic transmission. Glutamate receptor interacting proteins (interactors) serve dual purposes. They determine the level and site of glutamate receptor expression within the cells and connect the receptors to specific intracellular signalling pathways. Both roles are interesting from a therapeutical perspective.Thus, excitotoxicity might be alleviated by modulation of the surface expression of glutamate receptors, as well as by interfering with their downstream signalling. The first part of the project aims at providing a more complete picture of the functional roles of interactors (WP1-3). It is envisaged that we will be able to identify novel interactors and that we will be in a position to understand, at a molecular level, how the different interactors connect with glutamate receptors and with each other. This part of the project will also elucidate the principles that govern the turnover and surface expression of glutamate receptors and the mechanisms that couple the individual receptors to specific downstream effectors of excitotoxicity. The second part (WP4 and 5) aims at exploiting the increased insight obtained through the first part of the project to design ways to alleviate excitotoxicity in different model systems. In designing these experiments the complex of glutamate receptor interacting proteins will be viewed as a nodal point in orchestrating the surface expression of receptors and in activating appropriate and inappropriate (excitotoxic) signalling pathways. The present project will be based on a unique combination of methods that draws full advantage of the technological advances made over the last few years.
Project main goals

Excitotoxicity contributes significantly to neuronal cell death in a number of neurological conditions including stroke, head trauma, and Huntingtons disease.The recent discovery of proteins that anchor and interact with glutamate receptors opens a new strategic approach to cytoprotective therapy. The present project aims at exploiting this conceptual advance to provide a platform for cytoprotective therapies that do not interfere unduly with synaptic transmission.
Key issues
The main objective of the present project is to exploit the recent advances in this field to provide a platform for cytoprotective therapies that do not interfere unduly with synaptic transmission. Measurable objectives (detailed below) include: identification of at least five new proteins that interact with glutamate receptors; unravelling the precise mechanisms for at least five protein-protein interactions in supramolecular glutamate complexes; identification and characterisation of five different tools for interfering with protein-protein interactions; identification of at least ten putative pro-survival genes; evaluating the cytoprotective potential of the above tools and targets in in vitro models; test tools and targets with cytoprotective potential in whole animal ischemia models, ending up with at least three novel strategies with obvious clinical potential. The novel strategies thus identified will be of obvious commercial potential.The further development and clinical assessment of these is outside the scope of the present project. It is envisaged that the project as a whole will considerably increase our understanding of the molecular and cellular mechanisms and pathways in excitatory amino acid induced cell death and neuronal survival. This project is divided in two parts.The objective of the first part is to obtain a more complete picture of the functional roles of interactors.The objective of the second part is to exploit the increased insight obtained through the first part of the project to design ways to alleviate excitotoxicity in different model systems.In designing these experiments the complex of glutamate receptor interacting proteins will be viewed as a nodal point in orchestrating the surface expression of receptors and in activating appropriate and inappropriate (excitotoxic) signalling pathways.
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Technical approach
The project also has several objectives in relation to technology development. Thus we will: design and use blocking peptides to disrupt specific protein:protein binding events involving defined glutamate receptor subunits and, if appropriate, down-stream protein interactions; use and further develop fluorophore technology such as spectral variants of GFP, pH-sensitive GFP (pHluorin) and photoactivatable GFP (PA-GFP) to monitor protein movement in neurons; design and optimise siRNAs and hairpins for the targeted knockdown of specific proteins; exploit viral delivery systems for highly efficient expression of peptides, modified proteins or siRNAs in neurons in culture and in vivo; make use of existing and newly developed transgenic mice that either lack specific protein(s) or express modified versions of proteins of interest (e.g. epitope-tagged GluRs).
Partners
Henley, Jeremy Bristol University Senate House Bristol, United Kingdom Rnn, Lars Christian NeuroSearch A/S Ballerup, Denmark Kaczmarek, Leszek Instytut Biologii Doswiadczalnej im. M. Nenckiego PAN Warsaw, Poland Bading, Hilmar Heidelberg University Heidelberg, Germany Pin, Jean Baptiste
Expected achievements/impact
The potential impact of identifying novel strategies for cytoprotective therapy is enormous. After more than two decades of intensive research we are still left without a single cytoprotective drug for clinical use. Should we succeed in identifying novel approaches to curb excitotoxicity, and should these strategies eventually prove useful in a clinical setting, the impact would be on a par with the discovery of the first antihypertensive drugs.
Fluofarma SA Pessac, France Roepstorff, Peter University of Southern Denmark Odense M, Denmark Choquet, Daniel and Mulle, Christophe CNRS Paris, France
Coordinator
Petter Ottersen, Ole University of Oslo CMBN Postboks 1105 Blindern 0317, Norway Phone: +47 22851299 Fax.+47 22851488 E-mail: o.p.ottersen@medisin.uio.no
Bordeaux, France Davanger, Svend Universitetet i Oslo CMBN Blindern, Norway
Acronym: GRIPANNT Project number: LSHM-CT-2005-005320 EC contribution: 1 785 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/06/2005
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STRESSPROTECT
Inhibition of stress activated protein kinase signalling as a therapeutic strategy against exitotoxicity
Summary
Excitotoxicity (EXC), neuronal death from excessive stimulation, contributes to a plethora of neurodegenerative conditions including cerebral ischemia and seizure-induced death. Stress-activated protein kinases (SAPKs) of the JNK and p38 families have been identified as novel mediators of EXC death which is mainly executed by existing proteins demanding post-translational modifications. STRESSPROTECT members have (a) demonstrated that specific TAT-fused peptide inhibitors of the JNK pathway confer lasting neuroprotection against seizure-induced and ischemic cell death with an extended therapeutic window, (b) analysed the individual apoptotic actions of SAPK isoforms, and (c) provided important insights into signalling from glutamate-receptors. STRESSPROTECT gathers the European elite for SAPK signalling in the brain and for neuroprotection against EXC by pharmacological intervention in these pathways, and proposes a novel therapeutic concept against EXC. STRESSPROTECT provides synergistic research activities addressing the organisation and function of SAPKs signalling with molecular genetics, proteomics, signalosome-analysis, and molecular pharmacology including pharmacokinetics. At the end STRESSPROTECT has identified EXC-related SAPK signalosomes and delivered novel inhibitor peptides against SAPK signalling underlying EXC-mediated degeneration. STRESSPROTECT will identify (a) proteins in upstream regulatory complexes induced by EXC, (b) the downstream targets mediating EXC, (c) specific protein-protein interaction sequences as targets for functional inhibition of SAPK signalling, (d) extend the neuroprotective value of existing inhibitory peptides, (e) develop novel TAT-fused peptides inhibiting particular loci in the stress kinase pathways, (f) devise ways of targeting peptides specifically into EXC-affected cells and (g) carefully defines the risk-benefit ratio prospective to implementation in clinical trials.
Background
To achieve clinically useful neuroprotection against excitotoxicity (EXC) is currently one of the major challenges to medical research. It is the main mechanism underlying neuronal death in all hypoxic/ischemic and traumatic brain damage and in epilepsy, and contributes also to most neurodegenerative diseases.EXC is triggered by the excessive activation of ionotropic glutamate-receptors, particularly the NMDA (N-methyl-D-aspartate) subtype, but the propagation of intraneuronal signalling to degenerative execution remains obscure. Despite intensive study of the mechanisms of EXC and considerable success at neuroprotection in animal models, there are no approved current treatments against EXC in humans,and neuropharmacological treatments of epilepic disorders do not confer anti-excitotoxicity.The reasons for these failures are multiple, but we would mention two of the main problems. Unwanted side effects of the neuroprotection: drugs that inhibit the NMDA receptor itself cause psychotic-like reactions and memory loss in humans; and in animal models, while these drugs do rescue some neurons, they also cause the vacuolation and even the death of others. Shortness of the therapeutic time-window: these NMDA antagonists are generally found to be ineffective if given more than 2-3 hours after the onset of the ischemic event, which is too short for most practical purposes. Most of the neuronal death occurs much later than this 23 our limit, reflecting complex pathways between the initial calcium entry and the ultimate death effectors, and it seems plausible that a longer time window and a reduction in side-effects might be achieved by targeting specific stress-activated pathways well downstream of the initial calcium-activated events. Recently, this strategy has been adopted by members of this consortium, focusing on the c-Jun N-terminal kinase (JNK) pathway. This led to the demonstration that peptide inhibitors of the pathway protect against several forms of EXC, and in particular confer strong protection against ischemic cell death even when administered 6-12 hours after the insult. Despite the promise of this neuroprotective therapy, which could in principle already be extended to clinical trials, it has to be admitted that the underlying cell biology is still largely unknown and it is unclear whether it can be extended to other EXC-
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related conditions.Furthermore,there is evidence that a second MAP kinase pathway, p38, is also involved in cerebral ischemia and other excitotoxic conditions. And while no negative side-effects of the peptide inhibitors have so far been discovered, they cannot be discounted. Hence, more research is needed to clarify the signalling pathways involved in a variety of cell biological and clinically relevant excitotoxicity models,and techniques need to be developed to target specifically the cells and pathways responsible for excitotoxicityrelated degeneration while sparing healthy cells and pathways without deleterious action. The project will bring together cell and molecular biologists,cell death experts, neuropharmacologists and neurobiologists with expertise in cerebral ischemia and seizures and in behavioural analysis, to analyse the two main stress kinase pathways (JNK and p38) at molecular, cellular and system levels. The ultimate aim will be to develop neuroprotective peptide drugs and effective protocols to be evaluated in rodent models of focal cerebral ischemia and kainate-induced epilepsy.The projects goals addresses all the objectives. It proposes a novel therapeutic concept against excitotoxicity (EXC) in particular following ischemia and seizure. STRESSPROTECT will develop novel pharmacological inhibitors against stress kinases (p38 and JNK). STRESSPROTECT provides synergistic research activities addressing the organisation and function of SAPKs signalling with molecular genetics, proteomics, signalosome-analysis and molecular pharmacology including pharmacokinetics.
is very high, not only due to the high incidence of the disorder, but also due to its long-term detrimental consequences. In the United Kingdom,it has been calculated that the care for every patient affected by stroke costs more than 15 000 pounds over five years, informal care costs excluded. In Sweden and in the Netherlands, special computer or statistical models have been implemented in order to tackle the difficulties related to cost-evaluation of stroke at the national level. In the United States, is has been evaluated that the cost of stroke during 2003 will be $51 billion with more than $6 billion for informal care-giving. In Taiwan, it has been calculated that the median cost per patient can be multiplied by a factor of approximately 15 depending on stroke severity as assessed by the initial neurological score. As already discussed, current therapeutic strategies are hardly effective, difficult to use (mainly due to a short therapeutic window following stroke), and may have serious side-effects, including potentially lethal consequences.The advent of new therapies based on JNK inhibitors with negligible side-effects and extended therapeutic window may drastically influence both stroke consequences and societal cost.As already discussed, cell-penetrating inhibitors of JNKs proved to be protective when administered 6 to 12 hours after cerebral ischemia in neonatal and adult rodents. If confirmed in humans, such an extended therapeutic window would profoundly modify the treatment opportunities against stroke. Today, a limit of three hours after thrombolytic treatment strongly reduces the number of patients susceptible to benefit from the intervention.The extended neuroprotective effects of treatment using JNK inhibitors would dramatically increase the number of patients which could be treated before the end of the therapeutic window.As a consequence, JNK inhibitors do not simply represent a new treatment strategy with increased potency as compared with current therapies, but may increase the population of patients that may be treated. Finally, the identification of peptide sequences for inhibition of specific kinases signalling will open a novel field of pharmacological approaches and biological activities.
Expected results
EXC is involved in almost all neurodegenerative diseases and processes. Nevertheless, our proposal focuses on ischemia and kainate-induced seizures as classical models of EXC. In consequence, STRESSPROTECT exemplifies the potential impact of basic research on clinically relevant diseases. Cerebrovascular disorders constitute a worldwide health problem. According to the French College of Neurological Teachers, stroke constitutes the third largest cause of mortality, with about 150 000 new cases every year in France. In Belgium, the annual incidence of stroke falls between 200-230 per 100 000 inhabitants,with a mortality rate of 21% and 30% of affected patients becoming dependent on others. In Italy, the incidence of stroke is about 10 in 100 000, with less than 5% of strokes occuring in subjects younger than 45 years. In Switzerland, more than 12 000 new cases occur per year (AZPD Astrazeneca). In the United States, stroke ranks also in third position as a cause of death and more than 600 000 cases were recorded during 1997 (National Center for Health Statistics).It has been calculated that a stroke occurs every 53 seconds in North America.The cost of stroke
The development of domain-specific peptide inhibitors will selectively target pathological signalosoms with a limited risk for side effects.Such inhibitors might be useful for neurological and non-neurological diseases.
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Coordinator
Prof. Herdegen,Thomas Department of Pharmacology University of Kiel Hospitalstrasse 4 24105 Kiel, Germany Phone: + 49 431 597 3502 Fax: + 49 431 597 3522 E-mail:t.herdegen@pharmakologie.uni-kiel.de Key words: excitotoxicity, genomics, neurodegeneration, proteomics, stroke, stress kinases
Dr Coffey, Eleanor Turku Centre for Biotechnology Turku, Finland Dr Courtney, Michael Department of Neurobiology A.I.Virtanen Institute Kuopio, Finland Dr Hardingham, Giles Edward Department of Preclinical Veterinary Sciences University of Edinburgh Edinburgh, United Kingdom Prof.Vercelli,Alessandro Department of Anatomy University of Turin Turin, Italy
Partners
JDr Bonny, Christophe Unit of Molecular Genetics University of Lausanne Lausanne, Switzerland Dr Castagn,Vincent Porsolt SAS Le Genest-Saint-Isle, France Prof. Clarke, Peter Geoffrey Department of Cell Biology Lausanne, Switzerland
Acronym: STRESSPROTECT Project number: LSHM-CT-2004-005310 EC contribution: 1 499 560 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/01/2005
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INTERDEVO
Gene networks in cortical interneuron development: modeling interneuron function in health and disease
Summary
The neural assembly underlying the formation of functional networks in the cerebral cortex constitutes one of the most complex neuronal systems in the brain.Much of this complexity arises during development through the interaction of two distinct neuronal types,the glutamatergic projection neurons and aminobutyric containing (GABAergic) interneurons. Recently interneuron dysfunction has been associated with severe neurological and psychiatric disorders (e.g. epilepsy, schizophrenia and bipolar disorder). In order to achieve true progress in the understanding of cortical development and of neurological diseases associated with cortical interneuron dysfunction, a complete account of the development of its neuronal constituents is essential. In that sense, despite the detailed picture that is emerging about the development of cortical projection neurons, the mechanisms underlying the development of interneurons in the cerebral cortex have remained poorly defined.The overall goal of our project is to obtain a comprehensive definition of the cellular and molecular mechanisms controlling the development of cortical interneurons. With the information obtained from the analysis of the normal development of cortical interneurons,we also plan to generate mouse models to study the consequences of cortical interneuron deficiency. Thus, the study of cortical development is important, not only to further our understanding of this complex phenomenon, but because cortical malformations are now recognised as causing significant proportions of cognitive and neurological disorders. Until the discovery that projection neurons and interneurons of the cerebral cortex follow different developmental programmes (reviewed in Marn & Rubenstein Nat Rev Neurosci 2: 780-90, 2001), the analysis of cortical malformations was observed from a unitary perspective, i.e. gene mutations would affect equally the development of both projection neurons and interneurons, producing cortical dysfunction.The recent findings on the subcortical origin of cortical interneurons, however, have provided with a new standpoint to understand cortical disorders. In this new context, gene mutations affecting cortical projection neurons would not necessarily perturb the development of cortical interneurons, and vice versa. This later observation is extremely important for the understanding of complex cortical disorders, since it is becoming evident that gene mutations exclusively affecting the development of a given subtype of cortical interneurons would not cause macroscopic malformations in the cerebral cortex, and therefore would be impossible to detect with standard imaging techniques (e.g. fMRI). Obviously, the fact that the cerebral cortex looks grossly normal does not mean that its function is also normal. Indeed, dysfunction of cortical interneurons has been recently associated with severe neurological conditions (e.g.epilepsy), and important psychiatric disorders, such as schizophrenia or bipolar disorder (Benes & Berretta Neuropsychopharmacology 25:1-27,2001.). In schizophrenia, for example, morphological abnormalities are relatively subtle.Nevertheless,there is increasing evidence suggesting that GABAergic neurotransmission is altered in the prefrontal cortex of schizophrenic patients. Specifically, a number of post-mortem studies suggest that the number, distribution, neurochemistry or synaptogenesis of cortical GABAergic interneurons could be altered in schizophrenia (Lewis & Lieberman, Neuron 28: 325-34, 2000).Thus, elucidating the mechanisms that regulate development of cortical interneurons is likely to be essential for understanding and, eventually treating, major psychiatric disorders.
Migrating cortical GABAergic interneurons in culture.The image shows the typical morphology of migrating cells, with a long leading process and a short trailing process. Cortical interneurons have always the same morphology when migrating.
Aim
The general goal of the project is to obtain a comprehensive definition of the cellular and molecular mechanisms controlling the development of cortical interneurons.To reach this aim, we will take a multidisciplinary approach by combining novel bioinformatic and genomics applications, cutting-edge imaging techniques, and conventional cellular, molecular and electrophysiological methodologies. In addition, we will develop new genetic tools to engineer developmental models of cortical disorders involving interneuron deficiency.
Background
Defects in cortical neural circuitry are most likely to underlie important neurological and psychiatric illnesses, such as epilepsy, schizophrenia and major affective disorders. Remarkably, a rapidly growing body of data suggests that some of these defects may arise as a consequence of abnormal development of the cerebral cortex.
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Expected results
Successful execution of the project will result in: i) new knowledge of the mechanisms underlying the specification,migration and terminal differentiation of cortical interneurons, and ii) generation of new developmental models of cortical disorders resulting from interneuron deficiency.
Coordinator
Dr Marn, Oscar Consejo Superior de Investigaciones Cientficas and Universidad Miguel Hernndez Instituto de Neurociencias de Alicante
There is increasing evidence suggesting that research on the development of cortical interneurons is fundamental for understanding the etiology of a number of important human disorders, ranging from epilepsy or learning disabilities to major psychiatric illnesses such as schizophrenia, bipolar disorder or autism. In addition to increasing knowledge on the basic mechanisms controlling the development of cortical interneurons, our research programme goes one step further in trying to exploit the full potential of genome information to underpin applications to human health.Thus, the production of mouse models of cortical interneuron deficiency will have a clear impact on improving the diagnosis and understanding of human cortical developmental disorders.
Universidad Miguel Hernndez, Campus de San Juan 03550 San Juan de Alicante, Spain Phone: + 34 96 591 9384 Fax: + 34 96 591 9561 E-mail: o.marin@umh.es Key words: brain development, cerebral cortex, GABAergic interneuron, neurological disorders, epilepsy, schizophrenia, patterning, migration, synaptogenesis, neurophysiology
Partners
Foundation for Research and Technology Hellas, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Heraklion, Greece Medical Research Council, London, United Kingdom MRC Anatomical Neuropharmacology Unit, Oxford, United Kingdom Ecole Normale Superieure and Centre National de la Recherche Scientifique, UMR 8542, Rgionalisation Nerveuse, Paris, France Oryzon Genomics, Barcelona, Spain
Differentiated cortical neurons in culture.The image shows an example of one of the possible morphological phenotypes observed in differentiated cortical neurons. Multiple genes control the fate of distinct cortical interneurons, determining their morphology, location and connections.
Fundacin para la Investigacin Biomdica del Hospital Universitario Ramn y Cajal, Madrid, Spain Telethon Institute of Genetics and Medicine, Naples, Italy
Acronym: INTERDEVO Project number: LSHM-CT-2004-005139 EC contribution: 2 000 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/01/2005
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NeuroDisseminator
Neuroimaging laboratories sharing data through a database

Sagittal view of somatosensory activations from the NeuroGenerator database With metaresearch across studies, one may gain new knowledge about the cerebral cortex and its functions.New hypotheses can thus be made by combining the results from different functional experiments.This is only possible with the proper tools, such as the NeuroDisseminator visualiser and query tool.A possible application is to use the database to find new hypotheses about the cerebral cortex.
Summary
The NeuroDisseminator project aims at creating functional maps of the human cerebral cortex by analysing PET and fMRI studies in a homogenous way. The studies are submitted from collaborating laboratories in Europe, and the statistical results are stored on a database distributed on DVD to all contributors.
3D view of somatosensory activations from the NeuroGenerator database
Coordinator
Prof. Roland, Per Karolinska Institutet Division of Brain Research Department of Neuroscience Retzius vg 8, SE 171 77 Stockholm, Sweden Phone: + 46 8 5248 7785 Fax: + 46 30 90 45 E-mail: per.roland@neuro.ki.se Project web-site: www.neurogenerator.org Key words: PET, fMRI, database, cerebral cortex, functional neuroimaging
Background
The main objective in functional neuroimaging is to map the location of cerebral functions. However, a single study only reveals just a few functions for some regions while these regions are probably contributing to many more functions,together with other regions in a larger network. NeuroDisseminator solves this issue by collecting many functional PET and fMRI studies from a number of laboratories in Europe and analyses them in a homogenous way.The statistical results are stored in a database called NeuroGenerator, which can be accessed with a visualisation and query tool.It is possible for the submitters to access the database through the Internet and it is also distributed on DVD to all the contributors.
Aim
The overall aim of the NeuroDisseminator project is to create a functional map of the cerebral cortex.This is only possible by collecting many PET and fMRI studies.Thus,the NeuroDisseminator project now aims at increasing the number of studies in the NeuroGenerator database and distributing the database to the collaborators. Another goal is to perform research and develop ideas regarding meta-analysis of these studies.
Partners
Svensson Center for Parallel Computers Royal Institute of Technology Stockholm, Sweden
Expected results
The first version of the database has already been distributed,containing a fraction of the experiments collected so far.We expect to release a second version soon.Within the NeuroDisseminator project, we also expect to publish some meta-analysis studies
Acronym: NeuroDisseminator Project number: LSSM-CT-2003-504752 EC contribution: 400 000 Instrument: Specific Support Action Duration: 36 months Starting date: 01/01/2004
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EUROMEMO
First European meeting on molecular and cellular cognition

Summary
Molecular and cellular cognition is a rapidly moving research area which is at a crossroads between basic neurobiology and clinical neuroscience. At the end of 2002 a new scientific organisation, the Molecular and Cellular Cognition Society (MCCS,www.molcellcog.org), was established with the aim of facilitating exchanges between laboratories in this research field and to promote neuroscience at the general public level.This document deals with the organisation of the first European Meeting, as a satellite of the Federation of European Neuroscience Societies (FENS) meeting, effectively held in Lisbon on 8-9 July 2004.On day 1,the first oral presentation session was followed in the afternoon by a single poster session. On day 2, two oral presentation sessions were scheduled, for a total of 21 speakers, 100 posters and 300 participants.In addition to invited speakers coming from Europe, Japan and USA, one third of the oral presentation had been selected from posters. Eight fellowships were awarded to junior scientists allowing them to participate in the meeting. mance and/or low IQ scores. Finally, drug addiction and alcohol abuse are believed to have a strong cognitive component, significantly affecting relapse and mental dependence.The convergence between brain pathology and cognitive dysfunction is possibly even more evident at cellular and molecular level. It is widely believed that the large majority of mental disorders are complex and often chronic diseases, caused by maladaptive changes in information processing, which result in functional and often anatomical alterations at the level of neural circuitry and neuronal signalling.The field of molecular and cellular cognition has been one of the first contemporary neuroscience branches to combine molecular and behavioural approaches to study inter- and intracellular communication and to have significantly contributed to clarify long-term mechanisms of synaptic adaptation. Quantitative analyses of behavioural parameters by means of pharmacological and electrophysiological tools have been enhanced, starting from the early 1990s, by new powerful genetic techniques such as gene targeting and transgenesis in the mouse.These technologies have been introduced with enormous success and provided important experimental evidence that molecular changes in specific brain areas underlay changes in synaptic plasticity, cognition and behavioural responses. For instance, mouse mutants for the transcription factor CREB have been useful not only in determining the role of gene expression in memory formation and consolidation but also to study its role in brain diseases such drug addiction and mood disorders. Moreover, the technologies of conditional and reversible mutagenesis in vivo that have been especially developed in memory research to circumvent developmental side-effects of the mutations studied are now available to study long-term neural changes associated with neuropsychiatric disorders. Conversely, genetically modified mouse strains,such as knock-out for monoamine receptors, that were originally generated to study psychiatric disorders such as addiction and anxiety,may be also useful to dissect cognitive processes. The advent of post-genomic and proteomic analyses hold considerable promise for the study of the cellular and molecular events that regulate synaptic activity and behaviour. Identification of
Background
A major emphasis of the LifeSciHealth Priority area studying the brain and combating diseases of the nervous system, which must be implemented within the 6th Framework Programme, is fully justified by the increased prevalence of neuropsychiatric diseases in highly developed countries. Recent statistics considering disability rather than mortality in our society place eight brain disorders amongst the first ten most relevant diseases, including major depression, neurodegeneration (mainly Alzheimers and Parkinsons), alcohol and drug abuse. Despite the apparent heterogeneity at the clinical level, research in neuroscience of the last decade has clearly demonstrated that most of these brain disorders share some common symptoms at the level of cognition, which in a broad sense includes both explicit and implicit forms of learning and memory.Indeed,clinical assessment for depression and Alzheimers disease often consider loss of memory and emotional disturbances as important early pathological evidence while patients affected by other diseases such as Parkinsons and Huntingtons always manifest cognitive symptoms at end stages.Moreover,early onset disorders such as attention deficit hyperactivity disorder (ADHD), mental retardation and epilepsy invariably correlate in their severe forms with poor school perfor-
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i) Fostering European research in the field of molecular and cellular cognition The birth of the field of molecular cognition was in 1992 with the seminal papers of Alcino Silva (Susumu Tonegawas laboratory, Nobel laureate) and Seth Grant (Eric Kandels laboratory, Nobel laureate) on the CaMKII and Fyn protein kinases knockout mice, respectively. Although previous research by means of pharmacological inhibitors started to investigate the behavioural correlates of drug action, Silva and Grant for the first time demonstrated that the loss of intracellular signalling molecules may produce deficits in long-term plasticity and long-term memory. Despite the meteoric development over the last decade of this field in the USA, a significant lag exists in Europe, where only few laboratories have used molecular and genetic approaches to dissect cognitive processes in experimental animal models.This is particularly disappointing since European research has always been a leading force in neuropsychopharmacology, both in academia (e.g. Daniel Bovet, Nobel Laureate) and in pharmaceutical industries.The organisation of the first European meeting in Molecular and Cellular Cognition has therefore the crucial goal of helping to fill the gap between US and European research in this new field.Additionally, this important meeting will also promote interchanges among American and European laboratories. ii) Developing interactions between pharmaceutical industry and basic research Although it is always difficult for individual researchers to establish fruitful industrial connections as mentioned above, this is perhaps more so in the rapidly evolving field of molecular cognition, where there is great opportunity for translational research. It is obvious that the scientific platform we are proposing may provide the ideal setting for a closer interaction between the academic world and the European industries interested in neuroscience. iii) Interacting with psychiatrists, neurologists and neuropsychologists One of the main goals of our meeting is to create an interface between basic scientists and clinicians. Just as an example, the recent experimental evidence provided by Nader, Ledoux and Alberini that consolidated memories can be weakened by pharmacological treatment during subsequent recall have considerable clinical potential. However, rigorous clinical research is needed before these findings can be shown to be clinically relevant.Stimulating interactions with clinicians is therefore a priority of our proposal and their participation in the meeting is highly encouraged.
specific gene products in subsets of neurons that may be activated upon learning is a major technological and economical challenge which needs to be developed in collaboration with pharmaceutical companies. In this respect, one of the proponents of the present application has pioneered this approach. Our precise understanding at the cellular level of the molecular mechanisms underlying normal and pathological synaptic plasticity in discrete brain areas is readily becoming an essential goal for identifying new, more specific drug targets for innovative treatments.However,validation of new potential targets as well as the development of new drugs will necessarily require appropriate animal models, in which the relevant molecules have been either deleted from the brain or modified in their expression level, activity, or structure. Finally, to process all this information and integrate it in a coherent picture of the cognitive processes that range from molecules to mind, it will be necessary to exploit innovative neuroinformatic and statistical tools. For all these reasons we believe that the first European Meeting on Molecular and Cellular Cognition is an excellent opportunity for developing this research field in our continent and it will provide an opportunity for the clinical and pharmaceutical world, as well as for junior researchers,to interact with top scientists coming from Europe, North America and Japan.
Aim
Our aim is to provide a European forum for the development of molecular and cellular approaches to study cognition, emotion and behaviour.Furthermore,we believe that a significant integration at this level between basic science, pharmaceutical research and clinical science will provide theoretical and practical foundations for future treatments of neurological and psychiatric disorders.
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iv) Providing additional opportunities for women and eastern European scientists Women scientists are underrepresented, especially at the principal investigator and/or professorial level in most areas of science. Indeed, this is true in the field of cellular molecular cognition and we are working toward reverting this trend. For example, of the seven scientists involved in the organisation of the meeting, only two are women. In addition, with the future enlargement of the European Union to eastern European countries it is also a high priority for us to involve researchers from those nations.Therefore, we plan to act in two ways. First, we will provide fellowships to encourage female scientists and eastern Europeans workers to come to this meeting. Second, we will select their most interesting posters for oral presentations. Due to the often prohibitive costs of attending North American meetings, this may be the only chance for many potentially outstanding investigators from these groups to meet leading scientists in the field in such a context. This meeting will also be useful for establishing personal contacts as a prerequisite for future job opportunities (e.g. postdoctoral training) and collaborations.
In addition to this meeting,the Molecular and Cellular Cognition Society would like to continue to foster the field in Europe through future initiatives and meetings, as well as having a role in the education of the general public on key findings in the field, including their limitations and implications for health and society.We strongly believe that good science cannot be self-sustaining.On the contrary,the best of research can only be achieved by frank and open interactions between scientists and the general public.This is particularly true for issues concerning cognitive neuroscience, a natural focal point for discussion and debate for the humanities and the natural sciences. For example, philosophical and health-related questions, such as the mind-body problem, the role of psychoactive drugs in medicine and recreation, the impact of neuropsychiatric diseases and their medication,have a far-reaching impact on health, ethics, legislation and on society in general.
Coordinator
Brambilla, Riccardo Centro San Raffaele del Monte Tabor San Raffaele Research Institute Va Olgettina 58 20132 Milano, Italy Phone: + 39 0226 434 876 Fax: + 39 0226 434 767 E-mail: r.brambilla@hsr.it
Expected results and potential applications

The impact of brain disorders on cognition, emotion, behaviour and public health is enormous.Changing demographics in European countries makes it imperative to decrease the morbidity of the aged population. As the proportion of people over retirement age increases, so will the burden of supporting them, borne largely by those in the workforce. Reducing the morbidity of neurodegenerative diseases is clearly a critical public health issue in developed countries.Cognitive decline in the elderly is one of the most immediate and destructive symptoms, often being a prelude to dementia and loss of independence, putting a major burden on families and on the healthcare system. Similarly, the ability of people of working age and younger to contribute to society must be sustained. Psychiatric disturbances such as mood disorders and addiction to drugs and alcohol are a major impediment to this contribution,and one of the most destructive influences in society.This fundamental knowledge is a sine qua non,in the immensely complex field of psycho-therapeutics,for the creation of strategies which might decrease,if not eliminate problems arising from these disorders, that affect so devastatingly both the individual and society. Understanding the basic molecular and cellular mechanisms of normal and pathological brain function is now a key goal of animal model studies.Most currently available technologies have been applied in the field of learning and memory, in which quantitative and reproducible tests are available to measure objective behavioural outputs.While it is not predictable at present as to what extent which of these studies may lead to the discovery of new treatments for disorders of the nervous system, it is nevertheless very important that Europe foments the interaction between basic research,clinical research and the industrial world. Such interactions will provide the basis for effective translational research in the field of memory and cognition and at the same time will create new opportunities for developing small- to medium-size biotechnology companies devoted to specific tasks, such identification of early diagnosis tools for neurodegenerative diseases or discovery of drugs improving memory, mood or attention.
Project web-site: www.molcellcog.org Key words: molecular and cellular cognition, learning and memory, neuronal plasticity, psychiatric diseases
Acronym: EUROMEMO Project number: LSSM-CT-2003-503373 EC contribution: 19 650 Instrument: Specific Support Action Duration: 18 months Starting date: 01/06/2003
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ESNI course 2003
European School of Neuroimmunology (ESNI); 4th Teaching Course Barcelona

Summary
Neuroimmunology aims to define the mechanisms underlying the immune-mediated pathology of diseases in the central and peripheral nervous system.The final goal is to be able to prevent and/or treat these diseases, multiple sclerosis being the most prominent. The European School of Neuroimmunology (ESNI) has been established to be a European framework for continuous educational programmes in neuroimmunology,and also to promote trans-national research cooperation in the field. Yearly ESNI teaching courses have been a cornerstone to fulfil these aims. The objectives of the 4th ESNI Teaching Course in Barcelona in September 2003 were to improve both research and clinical practice through increased international cooperation and combine basic and clinical research groups working on translational projects.
Expected results
The 4th ESNI course took place in Barcelona, Spain, on 28 September 1 October, 2003. Each of the four days was organised as a major session on innate immunity and brain functions, neurodegeneration and immunoregulation, relevance of autoandibody research in neuroimmunology, and immunotherapy in neuroimmunology.There were 32 talks with speakers from 11 different countries.There were more than 250 participants, 95% from Europe, and 20% from eastern Europe.There were an equal number of female and male participants. Sixty travel grants were distributed, and nearly all participants from eastern Europe were assisted in this way. One half of the participants were medical doctors, one half basic scientists. The course was organised with formal talks, informal discussion sessions, and organised tables for lunch with the expert where the participants could choose their mentor and discussion partner.A CD-ROM was produced with the full scientific content from the teaching course. This was distributed to all participants. Questionnaires with free text comments were returned from a majority of participants.The followup work of the project has included planning of further ESNI teaching courses, neuroimmunological research and education activities, and joint projects within and outside the EU framework programmes.
Background
Neuroimmunology is a rapidly expanding field aimed to define the pathogenic mechanisms underlying immune-mediated disease of the central and peripheral nervous system. The final goal is to define targets to establish new and efficient therapeutic projects. Neuroimmunology is a translational field of research owing to its ability to study molecular and cellular pathogenic mechanisms, to establish animal models and to develop new therapeutic approaches. Major neuroimmunological diseases are multiple sclerosis, myasthenia gravis, paraneoplastic disorders, encephalitis, myelitis, Guillain-Barr syndrome and myositis. Disorders with neuroimmunological aspects are stroke, Alzheimers disease and Parkinsons disease. Neuroimmunological diseases are therefore major contributors to the burden of disease, loss of function, disability and lost life years in Europe.
The application of the results of this project should lead both to improved research in neuroimmunology and to better treatment, diagnosis and prevention of neuroimmunological disease.The course should foster international collaboration on high-quality projects and give increased knowledge and skills to all participants.The ESNI work should also increase the interest and awareness of the challenges within this field, and by this improve the framework for research and optimal clinical practice for neuroimmunological diseases.
Aim
The aim of ESNI and of the 4th ESNI course is to foster high-quality neuroimmunological research and collaboration throughout Europe. This will also improve good clinical practice. Improved co-operation between research groups in Europe, especially between neuroimmunology, neurogenetics and neuro-proteomics, was also an aim in integrating basic science and clinical topics in true translational research. Further aims were to improve co-operation between eastern and western Europe, and being aware of giving equal opportunities to female and male research participants.The teaching course should be a contact forum between senior and junior researchers, between basic and clinical research, building a transEuropean network.
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Coordinator
Prof. Gilhus, Nils Erik Department of Neurology Haukeland University Hospital 5021 Bergen, Norway Phone: + 47 5597 5000 Fax: + 47 5597 5165 E-mail: negl@helse-bergen.no Project web-site: www.esni.org Key words: neuroimmunology, teaching course, neuroscience, multiple sclerosis
Prof. Graus, Francesc Servicio de Nevrologia Hospital Clinic I Provincial Barcelona, Spain Prof. Probert, Lesley Laboratory of Molecular Genetics Hellenic Pasteur Institute Athens, Greece Prof.Willison, Hugh Department of Neurology Southern General Hospital Glasgow, Scotland
Partners
Prof. Montalban, Xavier Unitat de Nevroimmunologia Clinika Hospital Vall DHebron Barcelona, Spain Prof. Martino, Gianvito Department of Biotechnology San Raffaele Scientific Institute Milan, Italy
Acronym: ESNI course 2003 Project number: LSSM-CT-2003-502993 EC contribution: 50 000 Instrument: Specific Support Action Duration: 10 months Starting date: 01/07/2003
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FENS Forum 2004
4th Forum of European Neuroscience

Summary
The 4th Forum of European Neuroscience, held in Lisbon on 10-14 July 2004, was one of the largest European meetings in the field of basic and clinical neuroscience.Topics addressed ranged from genes and molecules implicated in brain function and dysfunction, to the physiopathology and therapy of diseases such as major neuropsychiatric and neurodegenerative disorders. A special emphasis was given to translational science, i.e. how recent basic scientific findings can rapidly and successfully contribute to significant advances in the management of brain diseases with a high individual and socio-economic impact. The Forum included nine plenary and 12 special lectures, 56 symposia, seven technical workshops and approximately 3000 poster presentations from over 4500 participants. Two special sessions took place, in association with the European DANA Alliance for the Brain, and with the European Brain Council. The main objectives of the Forum were: 1) to contribute to the advance of neuroscience research, especially in Europe, by bringing together experts from all over Europe and beyond, to present and discuss their latest findings with their peers; 2) to promote education in neurosciences, facilitating the participation of young researchers and PhD students, by providing specially reduced registration fees and stipends, and organizing one workshop on education in neuroscience in Europe; 3) to boost the collaboration and scientific networks between European laboratories, including eastern European countries, as stipends were available for both young and senior scientists from those countries. The Forum was particularly relevant to the objectives of the Specific Programme Integrating and strengthening the European Research Area, under the topic Specific brain research support actions. In addition, it contributed to the objectives of establishing a European Brain Research Area, as set out in a conference organised by the European Commission on September 2003.
Background
The Federation of European Neuroscience Societies (FENS) is a non-profit organization that includes over 15 000 European neuroscientists from all specialities in this field, affiliated in national neuroscience societies from 24 European countries (Armenia, Austria, Belgium, Czech Republic, Denmark, Finland, France, Georgia, Germany, Greece, Hungary, Israel, Italy, Norway, Poland, Portugal, Romania, Russia, Spain, Sweden, Switzerland, The Netherlands, Turkey, United Kingdom), as well as five monodisciplinary multinational societies (the European Behavioural Pharmacology Society, the European Brain and Behaviour Society, the European Society for Neurochemistry, the Federation of the European Psychophysiology Society and the International Behavioural and Neural Genetics Society). The FENS Council designated the Sociedade Portuguesa de Neurociencias (SPN) to organise the 4th Forum of European Neuroscience in Lisbon on July 10-14, 2004.The SPN is a non-profit scientific organization affiliated to FENS. The FENS Forums of European Neuroscience are the largest scientific meetings organized in Europe, and some of the largest in the world, in the field of basic and clinical neuroscience, attracting most European neuroscientists, but also scientists from all over the world.The scientific programme of the Forum was established by an independent international Scientific Programme Committee, composed of senior scientists from different fields of neuroscience and from many European countries. The scientific programme covered topics ranging from basic neurobiology, e.g. genes and molecules implicated in normal brain functioning, but also in numerous neurological and psychiatric dysfunctions, to the physiopathology and therapy of diseases such as epilepsy, Alzheimers disease or schizophrenia.
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Aim
The main objectives of the FENS Forum of European Neuroscience were: 1) to contribute to the advance of neuroscience research, specially in Europe, by bringing together experts from all over Europe, as well as from other continents, to present and discuss with their peers their latest findings; 2) to promote education in neurosciences, facilitating the participation of young researchers and PhD students, by providing specially reduced registration fees, grants and stipends, and organizing one workshop on education in neuroscience in Europe; 3) to boost the establishment of collaborations and scientific networks between laboratories all over Europe, including eastern European countries; special grants and stipends for participants from those countries will also be available; 4) to raise public awareness of brain research by disseminating to the general public the most relevant findings presented at the Forum, and by promoting a special symposium on Public Awareness of Brain Research. By bringing together such a large number of European neuroscientists, with different personal perspectives and levels of differentiation ranging from senior scientists to PhD students, an additional objective was to provide the environment for informal discussions on topics relevant to the promotion of European neurosciences, such as the promotion of an European Brain Research Area, the establishment of European Post-graduate Neuroscience Programmes, the improvement of post-doctoral activities in Europe in order to avoid the brain drainage, mechanisms for supporting post-docs working outside Europe to return to their own countries, etc.
The Forum represents a significant added-value to brain research in Europe,as specialists from all European countries had the opportunity to present to their peers their latest findings in virtually every field of the neurosciences. Neuroscientists from non-European countries also participated,further contributing to the advance of neurosciences in Europe and elsewhere. A special session, co-organised with the European Brain Council, was held on Brain Research in Europe: structuring European Neuroscience. New perspectives, as a followup to the meeting organised by the European Commission on September 2003 on Brain Research in Europe.
Coordinator
Prof. Castro-Lopes, Jos Sociedade Portuguesa de Neurociencias Instituto de Histologia e Embriologia Faculdade de Medicina do Porto Alameda Hernani Monteiro 4200-319 Porto, Portugal Phone: + 351 225 091 468 Fax: + 351 225 505728 E-mail: fens2004@med.up.pt Project web-site: www.fens2004.org Key words: neuroscience, scientific meeting, Europe, research
Expected results
The abstracts of almost 3 000 scientific communications were published in an abstract book (FENS Forum Abstracts, volume 2, 2004) that is citable and covered by Current Contents,Medline and all major indexing services. Abstracts are also available at the Forum website and on CD. Therefore, the presented research findings were disseminated to the entire scientific community, well beyond the participants of the Forum. A professional press office was in charge of spreading out to the general public the most relevant findings presented at the Forum. Moreover, a special symposium was dedicated to Public Awareness of Brain Research.
Partners
Prof Mervyn Bibb John Innes Centre, Norwich, United Kingdom
Acronym: FENS Forum 2004 Project number: LSSM-CT-2004-005100 EC contribution: 190 000 Instrument: Specific Support Action Duration: 15 months Starting date: 01/01/2004
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RABRE
Resource allocation to brain research in Europe

Summary
In this project the costs of brain disorders in Europe are estimated and a next step is suggested: analysis of the funding of brain research (neuroscience) in Europe. Both private funding and public funding will be analysed and divided into categories according to function or disease target.A comparison of the results will be made across countries within Europe, as with the USA and Japan. Furthermore, the project contains an assessment of the potential benefits of further funding efforts for neuroscience in Europe in relation to costs.Several methods for testing this will be used, and results from a another project on the economic burden of brain diseases in Europe will be used for comparison.The results from the assessments shall be compared with studies performed in other research areas and indicate the best possible use of funding allocation for research in Europe in future.These kinds of studies are missing in Europe, and hence this project shall be a pioneer in an area receiving more and more attention in the research community as well as in policy discussions in the European setting.
Aim
To investigate the funding resources for brain research in Europe and assess the potential benefits and costs related to neuroscience of further efforts for brain research in Europe in the future. More specifically the objectives of the study are to: 1. analyse the resources used for brain research (neuroscience) in Europe and to compare overall research efforts; 2. compare the size and allocation of funding for neuroscience in Europe with resources used in the USA; 3. assess the potential benefits in relation to costs of further efforts for brain research in Europe through several tests: a. relating the total current funding for brain research in Europe with the total economic burden of brain diseases in Europe b. assessing the value of brain research to health improvement and life expectancy in Europe c. assessing the cost-effectiveness of further funding for brain research in Europe 4. disseminating the above results to clinical and basic scientists,patients, politicians, other decision-makers and to people of Europe.
Background
Brain research has not been sufficiently high on the European agenda. The spending on brain research in Europe is much lower than similar spending in the United States or Japan, and is not commensurate with the burden of these diseases or to the importance of understanding the normal brain. It is generally accepted that Europe led in brain research until approximately 10 or 20 years ago. At that time this role was taken over by the United States and the gap between European brain research and United States brain research continues to widen. A similar consideration is true for Japan although this country produces a considerably lower quantity of brain research. Brain research is extremely important for the biotech industry, and drugs for brain diseases together represent the biggest single future indication for drugs.The present project will contribute to increase understanding of the importance of new treatments for brain diseases and, hopefully, via stimulating the interest in brain research and via increased and focused (and efficient) funding for brain research will help to increase European competitiveness in this field.
Expected results
The project will result in the best possible estimates of public and private research spending for brain diseases in Europe, as well as provide an estimate of the economic benefits for Europe from previous advances in brain research, and an estimate of the potential benefits from further investments in different areas of brain research. The RABRE project will provide a framework for assessing the value for society of medical research in general and brain research in particular, and set the stage for a discussion about priorities to and within brain research (neuroscience).
The results will be directly useful for legislators and administrators concerned with priorities for investments in life sciences and biotechnology for health.Moreover,it is expected that the results of the present study will be important for policy development both at European level as well as at national level in Europe.The results from the project will provide solid information on the value of further research in neuroscience in Europe. Hence, it is anticipated that the results shall be a basis for decision-makers in the political and scientific communities in Europe.
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Coordinator
Prof. Olesen, Jes European Brain Council Glostrup Hospital Department of Neurology Nordre Ringvej 2600 Glostrup Copenhagen, Denmark Phone: + 45 43 23 30 36 Fax: + 45 43 23 39 26 E-mail: jeol@glostruphosp.kbhamt.dk Project web-site: www.ebc-eurobrain.net Key words: brain disorder, brain disease, neuroscience, health economics, economics, epidemiology, funding, cost-benefit, cost-effectiveness, Europe
Partners
Prof. Jnsson, Bengt Stockholm Health Economics Stockholm, Sweden
Acronym: RABRE Project number: LSSM-CT-2005-013043 EC contribution: 300 000 Instrument: Specific Support Action Duration: 18 months Starting date: 01/01/2005
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Human development and ageing

MIMAGE GEHA EMBIC Cells into Organs LINK-AGE ANABONOS OSTEOGENE AGEACTION 142 144 146 148 150 152 154 156
HUMAN DEVELOPMENT AND AGEING
MIMAGE
Role of mitochondria in conserved mechanisms of ageing

Summary
The overall aim of this programme is to assess the role of mitochondrial function in ageing and lifespan control.The strategy used is to discover mechanisms that show evolutionary conservation between invertebrate and mammalian model systems.A unique matrix of model organisms (yeast, Podospora anserina, Caenorhabditis elegans, Drosophila melanogaster, mouse and rat) and cell culture systems is used. Specific questions will be experimentally tested.The following age-related issues are addressed: (i) modulation of mitochondrial reactive oxygen species (ROS) by different means, (ii) relevance of molecular and cellular pathways to maintain a healthy population of mitochondria, (iii) nature and impact of signalling pathways on mitochondrial activity, (iv) effects of dietary restriction on mitochondrial activity, (v) novel age-related mitochondrial functions. The participating laboratories have a strong commitment for collaborative work and ideally complement each other. Some of the partners extensively collaborated in the past or are collaborating presently in the field of research addressed in this IP. They are working with different model organisms and systems, most are well experienced in the field of experimental biogerontology,and they each have a specific expertise in different fields of research ranging from advanced biochemistry, cytology, genetics to molecular biology.This consortium is in the unique situation of performing competitive research with other programmes aimed at identifying and characterising mechanisms of ageing that are conserved in most species, hence called 'public' mechanisms of ageing. At the same time, the IP complements European activities that follow other strategies (e.g., comparing mitochondrial parameters from human tissues of different human populations) to elucidate the role of mitochondria in human ageing. war of the generations is expected.A solution will only be possible by an integrated approach: political decisions (e.g. restructuring social and health insurance systems) and substantial scientific advances to understand the basics of biological ageing and to use this understanding to intervene in the processes of ageing. Unfortunately, although in the last three decades more information about the molecular mechanisms of ageing have been established, in not one biological system are these mechanisms sufficiently understood in detail. However, it is generally accepted that major conserved or public mechanisms exist in addition to mechanisms which are species-specific or private. Unravelling the public mechanisms of ageing is thought to be of special importance because these seem to be the mechanisms of general relevance. Our strategy is to elucidate these mechanisms in various biological systems.At the organism level, the two fungi Saccharomyces cerevisiae (yeast) and Podospora anserina, the nematode Caenorhabditis elegans, Drosophila melanogaster, mice and rats offer important advantages for experimental research (e.g.short life-time,accessibility to genetic and molecular analysis) and therefore are preferred ageing models. In addition, cell cultures are investigated extensively.
Aim
The specific aim of this project is to unravel the molecular conserved mechanisms of normal or healthy ageing. The strategy is to use a variety of systems with a special emphasis on organismic ageing.These models are clearly independent complete organisms with a long history of evolution, but are much less complex in their organisation than humans. The consortium, however, does include sub-projects studying cell culture systems as well. As well as different cell cultures from normal subjects one important premature ageing model, Cockayne Syndrome, is included.The consortium covers a variety of ageing models,a prerequisite for the identification and characterisation of public ageing mechanisms. A very important advantage of the selected systems is that they are accessible to experimentation. Therefore, specific questions can be asked and, due to the short lifespan of some of the systems, can be addressed experimentally in a way that is not possible in higher organisms like humans. Moreover, a variety of long-lived mutants are available. The analysis of these mutants has contributed and will continue to contribute significantly to what is known about basic molecular pathways governing ageing. The consortium is in the situation of being able to go considerably beyond those investigations which in the past has generated a huge body of essentially correlative data.
Problem
Ageing as the progressive loss of function and consequently an increase in morbidity is a serious social problem.Today, social security and health insurance systems are collapsing. Almost every day new strategies to safeguard these systems (e.g. by increasing the rates to be paid by the individual) are discussed in politics and large parts of the European population are fear that their pensions will be lost in the near future.With an increasing proportion of the elderly in the population in the next decades this problem will keep growing and a
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Expected results
1.The establishment of efficient procedures for the isolation of coupled mitochondria in Podospora anserina and Caenorhabditis elegans. 2.The establishment of procedures for efficient measuring of reactive oxygene species in Podospora anserina and Caenorhabditis elegans 3.The establishment of procedures for the efficient identification of oxidatively damaged proteins and for monitoring mitochondrial lipid peroxidation. 4. Identication and definition of the impact of exogenous and endogenous factors/ components (e.g. uncoupling proteins, nutrition) which affect oxidative stress on mitochondrial functions and ageing. 5. Determination and characterisation of specific mitochondrial functions (mtDNA stability, mtDNA repair, heat shock proteins, turnover of mitochondria) affecting lifespan and ageing. 6. Demonstration that and how different signaling pathways (retrograde signalling, cAMP/PKA, and insulin/IG1 signalling) affect mitochondrial functions. 7. Identification and characterisation of additional (novel) age-related mitochondrial functions causatively linked to ageing.
Coordinator
Prof. Osiewacz, Heinz D Botanical Institute, Johann Wolfgang Goethe-University Marie-Curie-Str. 9 60439 Frankfurt, Germany Phone: + 49 69 798 29264 Fax: + 49 69 798 29363 E-mail: osiewacz@em.uni-frankfurt.de Project web-site: to be created Key words: ageing, mitochondria, model systems, reactive oxygen species, molecular mechanisms
Partners
Zoological Institute, Johann Wolfgang Goethe-University, Frankfurt, Germany Institute of Genetics, University of Salzburg, Austria Faculty of Chemistry, Physical Biochemistry,Technische Universitt Darmstadt, Germany Laboratory of Genetics,Wageningen University,The Netherlands Institute for Biomedical Aging Research, Austrian Academy of Sciences. Innsbruck, Austria
The general knowledge generated in this project may in the future be used to develop specific interventions into the ageing process of biological systems.
Acronym: MIMAGE Project number: LSHM-CT-2004-512020 EC contribution: 7 400 000 Instrument: Integrated Project Duration: 60 months Starting date: 01/01/2005
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GEHA
GEnetics of Healthy Ageing

Summary
GEHA will identify genes involved in healthy ageing and longevity, which allow individuals to survive to advanced old age in good cognitive and physical function and in the absence of major agerelated diseases.The work plan is: (i) to collect 2800 long-lived (90+) sibpairs and 2800 unrelated younger control subjects from ten European countries and China; (ii) to perform a genome scan in all the sibpairs (Affected SibPair Analysis, ASP) in order to identify new chromosomal regions harbouring putative longevity genes, followed by positional cloning and mutational analysis and preceded by LD block structure in CEPH families; (iii) to thoroughly investigate in cases and controls three candidate regions in chromosomes 4, 11 and 19 that according to previous studies are involved in ageing and longevity; (iv) all the recruited people will be genotyped for mitochondrial DNA haplogroups and C150T mutation known to play a major role in ageing and longevity. Gender-specific genes involved in healthy ageing and longevity in women and men stratified for ethnic and geographic origin and APOE genotype will be identified; a longitudinal survival study to assess the impact of the identified genetic loci on 90+ people mortality will be performed; mathematical and statistical models capable of combining genetic data with demographic characteristics, health status, socio-economic factors, lifestyle habit will be developed. can be found by studying the selected group that survives past age 90. A network of geriatricians, demographers, geneticists and statisticians is involved in GEHA to investigate the genetic basis of the ageing process in humans. It is predicted that in addition to new information on the genes governing healthy ageing, innovative bioinformatic algorithms, demographic/mathematical models and powerful statistical approaches will be developed as a result of GEHA.
Aim
Major goals of GEHA project are: 1. to recruit 2800 long-lived sibpairs and 2800 younger control subjects from 17 geographic areas for genome scanning in order to identify chromosomal regions involved in longevity and healthy ageing; 2. to perform bioinformatic,functional genomics and proteomics and molecular biology studies on the longevity regions/genes and gene variants resulting from ASP analysis and Linkage Disequilibrium (LD) mapping; 3. to test whether ethnically different populations share the same genes involved in ageing and longevity; 4. to verify if the genes involved in longevity and healthy ageing in the European population are the same in an ethnically different population such as the Chinese; 5. to ascertain the role played in human longevity by three candidate regions; 6. to verify in different populations the role of mtDNA haplogroups as putative genes affecting longevity, and to study their interaction with the newly emerging longevity nuclear genes; 7. to identify gender-specific genes differently involved in healthy ageing; 8. to stratify the sample according to APOE genotype, the only genetic marker which so far has been found to be associated with reduced longevity in a variety of populations; 9. to develop innovative analytical strategies capable of combining all the data collected (clinical,socio-economical,related to lifestyle, demographic and genetic); 10. to evaluate the importance of genetic factors on the mortality of the recruited sibpairs.
Problem
In 2000, 69 million people worldwide were aged 80 or over. This population is the fastest-growing segment of the population. By 2050 the 80+ years old group is expected to increase five-fold to 377 million and represent 4.4% of the population.The number of nonagenarians will reach 63 million by 2050, which is an eight-fold increase. Centenarians currently estimated at 167 000 will reach a projected 5.3 million worldwide. Europe is the area where population ageing is most advanced. This demographic explosion makes it critically important to identify the factors involved in ageing devoid of major diseases and disabilities, contributing to increase the number of old European citizens in good health.Clues concerning such healthy ageing
Expected results
The project should help in identifying biological and non-biological determinants of successful/unsuccessful ageing and longevity, and in particular genes and gene variants as new and innovative targets for diagnostic and therapeutic strategies of age-related pathologies and
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disabilities. These findings will represent a starting point for new activities to be developed and exploited by the European biotech companies which are part of the GEHA consortium. The following outcomes are expected: - development of ad hoc protocols, standardised at European scale, for the assessment of the health status of the oldest old; - development of new ad hoc algorithms capable of combining clinical, social and genetic data in order to identify subgroups of old people at higher risk for the development of age-related diseases/disabilities; - development of ad hoc microarrays for the assessment of successful/unsuccessful healthy ageing; - development of molecular biology methods capable of exploiting the knowledge related to the genes associated with healthy ageing and longevity to counteract the activity of genes related to major agerelated diseases and disabilities.
Coordinator
Prof. Franceschi, Claudio University of Bologna - CIG Via Zamboni 33 40126 Bologna, Italy Phone: + 39 051 2094743 Fax: + 39 051 2094747 E-mail claudio.franceschi@unibo.it Project web-site: http://www.geha.unibo.it Key words: healthy ageing, longevity, demography, affected sibpair analysis, linkage disequilibrium mapping, mitochondrial DNA, APOE, functional genomics, proteomics, gender, genetic ethical issue Partners 2 France 2 Germany 6 Italy 1 The Netherlands 1 Greece 2 Finland 1 Poland 2 United Kingdom 3 Belgium 2 Denmark 1 Peoples Republic of China
The genetic approach of GEHA, combining ASP analysis and LD mapping,is applied to a very large number of 90+ sib pairs and younger control subjects newly recruited across Europe. This experimental design will allow: (i) an independent genetic mapping of any chromosomal areas of special interest; (ii) a comparison between Sardinia (with its unusual enrichment of male centenarians) and Finland (with their unique genetic characteristics) with other European countries; (iii) a comparison of the data obtained on the genetics of longevity within European populations to those obtained by the Beijing Genomics Institute (BGI) on a large collection of DNA and clinical data regarding a totally different ethnic group such as the Han Chinese population; (iv) subgroup comparisons with respect to social and environmental factors.
Acronym: GEHA Project number: LSHM-CT-2004-503270 EC contribution: 7 200 000 Instrument: Integrated Project Duration: 60 months Starting date: 01/05/2004
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EMBIC
The control of embryo implantation. Studies of gene expression, protein profiles / functions at the utero embryonic level: Cellular and molecular developmental events at the fetomaternal interface
Summary
Understanding the cause of female infertility, as well as the molecular mechanisms of embryo implantation, is important for treating the former and increasing the success rate of IVF- ET. Discrete molecular implantation defects might also be the primary lesion in pre-eclampsia. EMBIC will network and structure leading but unlinked European groups so as to catalyse their efforts and maximise their potential. Recent advances in genomics and proteomics open the possibility of understanding what recent KO animal studies and clinical evidence highlight as being the main events controlling implantation. At present, fragmentation of experimental capacity and disparate approaches result in lack of a comprehensive skills base, and lack of access to very specialised approaches and technological platforms such as animal experimentation in very strict conditions, genomics and proteomics facilities or multicentric clinical evaluation. These require being used in a coordinated fashion to maximise their effect in this area. We will thus: 1. assemble critical talents and approaches, to develop an integrative, evaluative, capacity to set up EMBIC; 2. integrate EMBIC laboratories using crucial models and coordination of the joint programme of activities: 2.1. early embryo signalling to ultimately allow selection of only those embryos which will effectively implant; 2.2. key events in tissue remodelling; 2.3. homing/ proper activation of Natural Killer (NK) cells; 2.4. role of MHC class I gene products and their recognition by NK cells; 2.5. control of the inflammation complement related pathways; 2.6. cytokine/ chemokines/ profiling;
Problem
Female sterility is increasing in Europe and this is partly countered by Assisted Reproductive Technologies. In December 2002, the European in Vitro Fertilisation (IVF) Embryo Transfer (ET) monitoring programme reported in a study from 22 countries some 258 460 cycles of treatment. The success rate is stalled at present around 25% for IVF and 27% for ICSI (intra cytoplasmic sperm injection).As a partial consequence of the rise in infertility, compared with 1998, the number of cycles increased by 11%, and projections are for a similar increase in the 2003-2004 period. Understanding the cause of such a rise in female infertility is therefore of prime importance. Furthermore, the success rate of ET remains low, which is costly psychologically and financially. In most European member countries,a single cycle costs of the order of 3 000 to 5 000.In addition,as an empirical approach to improve implantation rates,several embryos may be transferred,normally resulting in a multiple pregnancy and delivery rate of 26.3% (most often,but not always,twins). Finally, discrete molecular implantation defects might be the primary lesion in pre-eclampsia, a high risk disease frequent in Europe and the major cause of maternal mortality (1.5 deaths /100 000 pregnancies), causing many associated maternal deaths in developing countries.Limiting factors to implantation seem to be the implantation window, the proper formation of a functional decidua basalis with intensive tissue remodelling (uterus), and de novo organogenesis (placenta formation).
Aim
We aim to build an European virtual laboratory on major mechanisms of implantation by thoroughly exploring what knock out mice have recently established as cellular-cytokine networks/ key pathways promoting the development of two de novo organs: the decidua basalis and the mature placenta.
A murine pre implantation uterus labelling with DBA lectin reveals it is composed at 80% of activated lymphocytes of the natural killer cells lineage
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2.7. invasion and early post-implantation events, Matrix Metallo Protease (MMP) based proteolysis/ adhesion molecule functions. 3. constitute a European cohort of infertile women with creation of RT generated DNA, sera and micro-biopsy tissue samples banks; 4. establish guidelines for management of infertile women combined with diagnosis procedures and ultimately recombinant technologies therapies for selected pathologies; 5. open the network of validated platforms for education and cooperative experimentation. EMBIC will contribute and benefit from the creation of integrated platforms based on animal models, genomic and proteomic facilities, protein intra-net database set-up and integrated clinical set-up.EMBIC will spread excellence by facilitating the exchange of scientists within the laboratories, promote recruitment/training of out-network postdocs, organise workshops and satellite meetings in pan-European or regional immunology/fertility meetings and an annual summer school.
Coordinator
Dr Chaouat, Grard Unit 131 INSERM Equipe cytokines et relation materno foetale Maternit Hpital Antoine Bclre 92141 Clamart CEDEX, France Phone: + 33 14 537 4450 Fax: +33 14 537 4450 E-mail: gerard_chaouat@wanadoo.fr Project web-site: www.embic.org Key words: embryo, implantation, signals, HLA-G, NKs, inflammation, complement, arteries, spiral
Expected results
We believe that we will answer the following questions: 1) Which preimplantation embryo signals permit only some embryos to implant in a receptive uterus? 2) Why is there such a high proportion of NK cells in the implantation uterus, a percentage higher even than that seen in lymph nodes? 3) What is their origin? 4) Which embryonic cell surface soluble factors signals induce the proper NK activation vs. an abortogenic one? 5) What are the cellular and molecular determinants of a tolerant uterus? 6) Which molecules/cells control early stroma remodelling and tissue differentiation (particularly spiral arteries)? 7) What controls trophoblast invasion and differentiation? 8) Which uterine growth factors permit proper placental differentiation (essentially at trophoblast level) and growth?
Partners
4 France 2 United Kingdom 1 Spain 4 Italy 2 Hungary 2 Germany 1 Belgium 1 Austria
Acronym: EMBIC Project number: LSHM-CT-2004-512040 EC contribution: 7 400 000 Instrument: Integrated Project Duration: 48 months Starting date: 01/10/2004
Screening of the embryos to determine those which will implant, improvement of IVF ET success rate,determination of new strategies for IVF-ET management, identification of genetic defects in sterility, understanding local uterine angiogenesis,insights into the mechanisms of pre-eclampsia. It is also expected that we will identify new gene expression defects causing female sterility as well as define therapeutic approaches and diagnostic tools.
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Cells into Organs
Cells into organs: Functional genomics for development and disease of mesodermal organ systems
Summary
This network will elucidate molecular and cellular processes underlying specification and differentiation of mesodermally derived organ systems. We integrate developmental genetics and experimental embryology with modern cell biology and genome scale analysis. These new technologies will enable us to identify genes which function in building a specific organ or in a particular aspect of embryogenesis. A major revelation of developmental biology has been the extent to which molecular strategies are redeployed,even during regeneration.Thus this information is the basic knowledge required for organ and tissue engineering. strategies are redeployed, not only at different sites during embryogenesis, but also during later tissue regeneration, is essential for understanding and eventually correcting,by appropriately targeted therapeutics,any malformation or deregulation which affects the adult organ and is the basic knowledge required for organ and tissue engineering.It will enable identification of the gene cascades associated with deadly or disabling genetic diseases and of suitable target genes for drug discovery.It will point the way for making specifically tailored stem cells for a multitude of therapeutic applications and for organ development in vitro.
Expected results
- We will sustainably integrate the participating groups into a durable world force in this area. - We integrate users and facilities into the networks Joint Technology Platform. - We develop a Joint Programme of Research which will generate important publications and joint initiatives during the networks lifetime - We organise a series of network symposia and a series of summer schools. - At least 20 completed PhDs will emerge from the network over its lifetime, as will a number of new independent groups. - We expect the network to generate industrial applications/ patents as saleable technology.
Problem
The development of new approaches to treating disease will revolutionise health care in the coming decade.Treatment of cancers will increasingly rely on targeted molecules rather than cytotoxic drugs. Manipulation of stem cells for cell and tissue replacement therapies holds great promise for treatment of degenerative disease and injury. Both approaches depend critically on detailed knowledge of the molecular and cellular events governing normal differentiation of the target organs and tissues. This knowledge provides the basis for organ and tissue engineering. Many important diseases affect organ systems such as heart, vascular system, blood, kidneys, skeleton, and musculature - deriving substantially or exclusively from mesodermal cells. Heart failure and strokes resulting from atherosclerosis, kidney failure, muscular dystrophy, osteoporosis, tumours and leukaemia are caused either by defects in development of these mesoderm containing organ systems or in their function, frequently as a consequence of ageing. Together, these diseases represent principal obstacles to reaching a healthy old age.
Genomic and postgenomic approaches will be applied to understand human development and ageing.This will develop the evidence base for improving public health strategies to promote healthy development and ageing.
Aim
The aim of this network is to integrate the established methodologies of developmental genetics and experimental embryology with the sophisticated approaches of modern cell biology and the new methodologies of genome scale analysis made possible by genome sequencing projects.These new technologies will enable us to identify many of the genes which function in building a specific organ system or in directing a particular aspect of embryogenesis.Analysing these genes,investigating their functions,and placing them in developmental cascades as well as following the cells which they affect, will undoubtedly reveal new aspects of organ development,extending and completing the existing picture. The extent to which molecular
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Coordinator
Dr Durston, Anthony J. The Netherlands Institute for Developmental Biology Uppsalalaan 8 3584 CT Utrecht,The Netherlands Phone: + 31 30 212 1800 Fax: + 31 30 251 6652 E-mail: tony@niob.knaw.nl Project web-site: www.cellsintoorgans.net Key words: organogenesis, stem cells, mesodermal organs
Dr Jacinto, A, Dr Thorsteinsdottir, Solveig, Dr Palmeirim, Isabel and Dr Rodrguez-Len, Joaqun Instituto Gulbenkian de Ciencia/Fundacao Calouste Gulbenkian Oeiras, Portugal Dr Jaeckle, Herbert Max-Planck-Gesellschaft zur Foerderung der Wissenschaften e.V. Max Planck Institute for Biophysical Chemistry Gttingen, Germany Dr Wagner, Erwin and Dr Hartmann, Christine Forschungsinstitut fur Molekulare Pathologie Ges. M.b.H. Research Institute of Molecular Pathology Vienna, Austria Dr Affolter, Markus and Dr Gehring,Walter University of Basel Basel, Switzerland Dr Duboule, Denis University of Geneva Department of Zoology and Animal Biology Geneva, Switzerland
Partners
Dr Deschamps, Jacqueline and Dr Korswagen, Rik The Netherlands Institute for Developmental Biology Utrecht,The Netherlands Dr Grosveld, F, Dr Dzierzak, Elaine and Charit, Jeroen Erasmus University Medical Centre Rotterdam,The Netherlands Dr Gurdon, John and Dr Smith, Jim The Wellcome Trust/Cancer Research United Kingdom Gurdon Institute of Cancer and Developmental Biology Cambridge, United Kingdom Dr Ingham, PW, Dr Borycki,Anne-Gaelle and Dr Roehl, Henry The University of Sheffield Sheffield,, United Kingdom Dr Stern, C and Dr Wolpert, Lewis University College London London, United Kingdom Dr Buckingham, Margaret and Dr Nicolas, JeanFranois Institute Pasteur Paris, France Dr Cossu, Giulio Fondazione Centro San Raffaele Del Monte Tabor, Milan, Italy
Acronym: Cells into Organs Project number: LSHM-CT-2003-504468 EC contribution: 7 200 000 Instrument: Network of Excellence Duration: 60 months Starting date: 01/04/2004
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LINK-AGE
Coordination and consolidation of European Biogerontology: en route towards formation of a European College of Biogerontology
Summary
Coordination and Consolidation of European Biogerontology will represent a step forward en route towards the formation of a European College of Biogerontology. LINK-AGE will be a Coordination Action building upon, and very significantly extending, existing European research in this field. Such research is still fragmented,limiting the ability to progress in an area of great economic and social importance for the future of Europe. LINK-AGE will provide an open, transparent mechanism to integrate research by addressing the following core objectives: 1) To identify common research strategies that will generate critical mass and added-value from European biogerontology research. 2) To establish a process that will help bring new researchers into the field from new geographical regions within the wider European community. 3) To establish a process that will bring new researchers into the field from other research areas within life sciences and health of relevance to ageing and longevity. 4) To establish a framework that will allow effective integration of research on different species to maximise the opportunities for synergy and interaction between researchers working on such species. To meet these objectives, LINK-AGE will support a closely coordinated programme of topic working groups, workshops and conferences, summer schools, and dissemination activities. Through its dissemination activities,it will develop effective links with the wider public and industry, in order that translation into benefit of emerging knowledge of the underpinning science of healthy ageing can be exploited as rapidly as possible. the underpinning science of biological ageing, in order that it shall be possible to minimise dependency and improve quality of life for the rapidly growing numbers of older people. Recent advances indicate that it is possible to intervene positively in the mechanisms that cause age-related frailty, disability and disease, particularly by developing and exploiting the fields of genomics and biotechnology for health in old age.These fundamental advances in science and technology offer exciting opportunities to extend health span (period of good quality life and functional \independence) and to develop European industry addressing the challenges of age. At present, European research capacity in biogerontology is still fragmented although efforts have been made through the Integrated Project programme of the European Union. This limits ability to make progress and results from several causes. First, the biology of ageing is itself inherently complex,with targets for study at many levels from molecules to cells to tissues to whole organisms, and in many different biomedical contexts (e.g. dementia, osteoporosis, visual impairment, declining immune function, etc). Second, in view of the practical advantages of working with shortlived model organisms, research is currently being conducted on a wide range of species (fungi, invertebrates, rodents, other mammals, birds) as well as humans. Biogerontology intrinsically requires integration of research across different biological levels, species, and biomedical contexts (e.g. it is likely that some of the same fundamental mechanisms are shared). Therefore there is need for a new coordination action that aims: (i) to achieve stronger integration and effectiveness within the field; (ii) to develop links between basic research and industry, particularly to help stimulate the success of existing SME's or new SMEs; (iii) to include and to support the participation of scientists across the full geographical span within Europe, particularly including scientists from candidate and associate states of the EU.
Aim
Scientific coordination The objectives of LINK-AGE in terms of scientific coordination are:
Problem
Europe faces the immense challenge of unprecedented increase in life expectancy, which will continue into the 21st century.Although this state of affairs is the essentially positive outcome from multiple improvements in health care and socioeconomic circumstances, it nevertheless presents great strains for all member and associated states of the European Union in terms of increasing prevalence of age-related health problems and the growing financial implications for pensions, etc.There is urgent need for more basic research on
a) To identify and help implement common research strategies that will generate critical mass and added-value from European biogerontology research. b) To establish a process that will help bring new researchers into the field from new geographical regions within the wider European community. c) To establish a process that will bring new researchers into the field from other research areas within life sciences and health of relevance to ageing and longevity.
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d) To establish a framework that will allow effective integration of research on different species to maximise the opportunities for synergy and interaction between researchers working on such species. Technical coordination The objectives of LINK-AGE in terms of technical coordination are: a) To establish a category of associate membership of LINK-AGE for those wishing to make connections with the field, but whose work does not yet meet the criteria for quality and relevance. b) To use the membership structure to draw into the membership of LINK-AGE researchers from diverse geographical regions within Europe, particularly those previously disadvantaged in access to scientific research support. c) To develop and support a series of LINK-AGE, conferences, and summer courses to address the scientific objectives. d) To establish an organizational framework for LINK-AGE to meet its scientific and technical objectives and to validate the concept of a distributed network of excellence in biogerontology research across Europe.
Coordinator
Dr.Toussaint, Olivier FNRS Research Associate University of Namur (FUNDP) Research Unit on Cellular Biology (URBC) Rue de Bruxelles, 61 B-5000 Namur, Belgium Phone: + 32 81 724132 Fax: + 32 81 724135 E-mail: olivier.toussaint@fundp.ac.be http://www.fundp.ac.be/urbc
Partners
Prof.TBL Kirkwood University of Newcastle upon Tyne, U.K. Prof. M. Blasco Spanish National Cancer Centre, Spain Dr. G. Butler-Browne Universit Pierre et Marie Curie, France Dr. ES Gonos National Hellenic Research Foundation, Greece Prof. E. Slagboom Leiden University Medical Center,The Netherlands Prof. J.Vanfleteren University of Gent, Belgium Prof. R. Contreras Flanders Interuniversity Institute for Biotechnology, Belgium Prof.T. Nystrom University of Gteborg, Sweden Prof. CC Zouboulis Charite Universitaetsmedizin, Germany Prof. HD Osiewacz Johann Wolfgang Goethe-Universitt,Germany Dr. M Salmon Straticell Screening Technologies, Belgium Prof. C. Franceschi University of Bologna, Italy Prof BFC Clark University of Aarhus, Denmark
Potential impact
Research that can lead to novel intervention to extend the health span and improve quality of life at older age has the potential for enormous impact in an ever-ageing society. Furthermore, the growing anxiety and fiscal threat posed by increased pension costs is founded on biodemographic models of ageing that urgently need updating by better informed knowledge of the ageing process and projections for future life expectancy. The scientific impact of the project will come from integrating the currently fragmented research activity within Europe.The diversity of European research traditions is potentially a rich resource for a topic as multi-faceted as biogerontology, but only if these diverse elements communicate with each other and develop ways of working together. It is only recently that researchers in other fields of biomedical research related to middle and late life degenerative conditions (e.g. dementia, cancer, cutaneous biology) have begun to recognise that since age tends to be the single biggest risk factor for the condition they are studying, understanding why the aged cell or organ is more vulnerable to pathology is likely to enable major breakthroughs. LINK-AGE will impact on this hitherto under-recognised need by encouraging many more researchers to participate in coordinated work that connects the study of age-related conditions with the underpinning mechanisms of ageing. It is now clear that ageing itself is the result of progressive, lifelong accumulation of a variety of molecular and cellular damage. This implies that ageing is a process that operates cumulatively across the life course and therefore events that happen at any age, even in utero, can have a major impact on an individual's expectation of length of life and of health in old age. LINK-AGE will encourage more researchers to address the links between early and late-life processes.
Acronym: LINK-AGE Project number: LSHM-CT-2005-513866 EC contribution: 1 100 000 Instrument: Coordination Action Duration: 48 months Starting date: 01/12/2005
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ANABONOS
Molecular Mechanisms of Bone Formation and Anabolism

Summary
Drug treatments which enhance bone formation are likely to be more effective than antiresorptive treatments in the treatment of patients with established osteoporosis.With this in mind, the present project aims to advance understanding of the mechanisms responsible for bone formation, with the long-term aim of harnessing this knowledge to develop new anabolic agents for osteoporosis. We will define downstream effectors of molecules that regulate bone formation in experimental models and identify the signalling pathways that are activated in human genetic diseases characterised by increased bone formation. The mechanisms of action of drugs with known anabolic effects will be investigated and novel genes that regulate bone formation will be uncovered by ENU mutagenesis and genetic mapping studies. The project will lead to a greater understanding of how bone formation is regulated and will underpin the development of new therapeutic strategies for the prevention and treatment of osteoporosis.
Aim
The aim of the project is to gain better understanding of the mechanisms by which bone formation is regulated with the aim of identifying new molecular targets that will form the focus for new therapeutic strategies for the management of osteoporosis.This will be achieved by investigating the transcriptional regulation of key target genes that play a role in regulating bone formation; by defining the effector molecules that are transcriptionally regulated by drugs and endogenous signaling factors that stimulate osteoblast activity and by defining the signalling pathways that are activated in human genetic diseases characterised by increased bone formation.Novel genes that regulate bone formation will be identified by positional cloning studies in experimental models which show a bone phenotype as the result of ENU mutagenesis.
Expected results
1. Better understanding of the mechanisms by which genes that promote bone formation are regulated at a transcriptional level. 2. Identification of a common set of target genes that are regulated by potentially anabolic drugs and endogenous factors that promote bone formation. 3. Generation of experimental models that will provide proof of concept that genetic manipulation of putative anabolic molecules can promote bone formation in vivo. 4. Identification of novel genes that regulate bone formation by classical positional cloning studies.
Problem
Osteoporosis represents a major disease burden in Europe and occurs because there is relative uncoupling between the amount of bone removed by osteoclastic bone resorption and that which is replaced by new bone formation. Most of the drugs that are used to treat osteoporosis act by inhibiting bone resorption and there is only one treatment available (the 1-34 fragment of parathyroid hormone) that works by stimulating bone formation. Antiresorptive therapies are highly effective agents for the prevention of osteoporosis, and also reduce the risk of fracture in patients with established osteoporosis. They work less well in patients with more advanced disease,however, because they are incapable of replacing bone tissue that has been lost as the result of the osteoporosis.
The molecules and target genes that are identified by this project will represent a new generation of molecular targets that can potentially act as anabolic drugs themselves, or can act as targets for the design of new drugs that enhance bone formation.The project will therefore be of value in helping to develop new treatments for osteoporosis with associated benefits for citizens who suffer from this disabling disease, in the European Community and beyond. It is also anticipated that new intellectual property will be developed during the project which could have positive implications for generating income for the higher educational institutions and commercial companies that are taking part in this project.
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Coordinator
Prof. Stuart, H Ralston MR FRCP FmedSci ARC Professor of Rheumatology Rheumatic Diseases Unit University of Edinburgh Western General Hospital Edinburgh EH2 2XU, United Kingdom Phone: +44 131 537 1088 Fax: +44 7714 266 616 E-mail: stuart.ralston@ed.ac.uk Project web-site: http://www.abdn.ac.uk/anabonos Key words: osteoporosis, bone formation, anabolic, parathyroid hormone, osteoblast Dr Garcia,Teresa Proskelia Pharmaceuticals Romainville Paris, France Dr Grigoriadis, Agi Department of Craniofacial Development Kings College London Guys Hospital London, United Kingdom Dr Gannon, Frank EMBL Heidelberg Heidelberg, Germany Dr Wagner, Erwin Research Institute of Molecular Pathology IMP Vienna, Austria Dr Sedlmeier, Reinhard Ingenium Pharmaceuticals AG Martinsried, Germany Dr Ferrari, Serge Geneva University Hospital Geneva, Switzerland Dr Mundlos, Stefan Research Group Development & Disease Max Planck Institute for Molecular Genetics Berlin, Germany Dr Hrab de Angelis, Martin GSF National Research Centre Munich, Germany
Partners
Dr van Hul,Wim Department of Medical Genetics University of Antwerp Antwerp, Belgium Dr Charnay, P INSERM U368 Ecole Normale Superieure Paris, France Prof. de Vernejoul, Marie-Christine INSERM U606 Hpital Lariboisir Centre Viggo Petersen Paris, France Dr Levi, Giovanni CNRS UMR5166 - MNHN Evolution des Rgulations Endocriniennes Paris, France Dr Lwik, Clemens Department of Endocrinology C4R Leiden University Medical Centre Leiden,The Netherlands
Acronym: ANABONOS Project number: LSHM-CT-2003-503020 EC contribution: 3 000 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/03/2004
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OSTEOGENE
Molecular mechanisms of bone homeostasis

Summary
Osteoporosis (OP) is a metabolic bone disease characterised by loss of bone mass and disturbed bone microarchitecture compromising bone strength and thereby pre-disposing for fractures. OP is a major health problem and of increasing concern in the European Community.The disease shows a strong gender bias in which genetic predisposition is important and a major predictor of our ability to reach and sustain optimal bone mass.The current project is focused on improving the understanding of the molecular mechanisms involved in bone homeostasis, and a main emphasis will be on the anabolic aspects. New knowledge is sought using contemporary array technology and functional genomics building on the recently definition of the human genome.A major target will be identification of the mRNAs and proteins that exercise a central role in the building (anabolic) phases of bone metabolism, including but not limited to those regulated by parathyroid hormone. Selective stimulation of anabolic effectors will, it is argued, form the basis for new treatment modalities that will increase new and fully-functional bone formation. This approach contrasts with many contemporary regimes of treatment that primarily inhibit bone resorption, thus increasing the amount of more or less worn tissue.A special attempt will be made to identify genetic markers that can be used for early identification of people at risk for later development of osteoporosis. Primary OP is a disease of unknown aetiology that is usually divided into postmenopausal and age-related OP although there are unifying features.The broad argument is that the dynamic processes of bone remodelling that comprise bone homeostasis have somehow failed. The conventional view is that the balance of production of bone by means of osteoblasts cannot compensate for bone resorption due to the activities of osteoclasts. These overall facts are clear and parathyroid hormone (PTH) has been recognised as not only a potential catabolic influence but also therapeutically available as an anabolic influence. The molecular composition of the bone extracellular matrix in OP is considered largely unaltered,but surprisingly little attention has been paid to this aspect.
Aim
The driving force for this project is that the molecular mechanisms causing or leading to OP are not sufficiently known to create substantial evidence-based knowledge for early diagnosis, prevention or causal treatment of the disease.Thus a main aim of the project is to combine genomic data (sequence and microarray expression data) with functional genome research and proteomics directed at identifying anabolic target genes in the skeleton. In this way the OSTEOGENE initiative seeks to provide a link between gene function
Problem
Bone is a dynamic tissue that is continually remodelling throughout life. In all ageing people this profit and loss process favours loss of bone mass. Consequently, many develop osteoporosis with considerably enhanced susceptibility to fractures with up to 30% mortality and massive, lasting morbidity. In fact, OP represents the most prevalent and incapacitating disease of women after 50 years of age and the increased incidence of the disease also among men has made it a serious threat to healthy ageing of both genders in Europe.
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and disease as a frame-work for stimulating biomedical commercial activities in the areas of early diagnosis, prevention and treatment of OP. The project will be undertaken by a multidisciplinary team including medical practitioners, molecular and cellular biologists and biochemists, all with an inter-national track record. The long-term aim will be a reduction in the impact of OP in Europe brought about by application of appropriate evidence-based therapeutic and preventive medicine.
Coordinator
Prof. Gautvik, Kaare M Department of Clinical Biochemistry, Division of Laboratory Medicine Ullevl University Hospital Kirkeveien 166 0407 Oslo, Norway Phone: + 47 957 42 125 Fax: + 47 22118189 E-mail: kaare.gautvik@basalmed.uio.no Project web-site: Not yet operative Key words: osteoporosis, gene profiling, bone anabolic effectors, genetic polymorphism
Expected results
The results of this project will substantially add to the existing knowledge base regarding: 1. association between genetic polymorphism and development of OP in humans; 2. possible identification of OP disease genes through genetic and post-genomic studies in man and animals; 3. improvement of basic insight into osteoblast and osteoclast regulation and their matrix interactions, and intra-/intercellular molecular signalling as it relates to bone remodelling; 4. the chemical nature and significance of bone matrix proteins and their molecular interaction in the bone remodelling process; 5. the bone remodelling process and its regulation by key anabolic effectors including PTH; 6. genes and gene products that are associated with or causally linked to bone formation.
Partners
Institute of Pathology, University of Oslo, Rikshospitalet University Hospital, Norway Endocrine Section, Department of Medicine, Rikshospitalet University Hospital, Norway Department of Cell and Molecular Biology, Section for Connective Tissue Biology, Biomedical Centre, Lund University, Sweden Division of Bone Disease, University Hospital, Geneva, Switzerland School of Clinical Laboratory Sciences, University of Newcastle,The Medical School, United Kingdom Department of Experimental Medicine, School of Medicine, Bone Biopathology Laboratory, LAquila, Italy Immunodiagnostic System, Boldon, United Kingdom
The project describes how to obtain for the first time an overview of OP-associated and -related genes and gene products defining a risk profile or genetic susceptibility. This strategy will form the basis for developing a diagnostic genetic test for the early detection of OP carried out on the mRNA or protein level. The projected objectives and deliverables represent major contributions to the medical diagnosis, care and treatment of OP compared to the present state-of-the-art where OP is underdiagnosed and detected late in the disease, frequently not until the first fracture. An expected outcome after compiling, analyses and verification of the data, is the capacity to move towards development of a genetic test for the early diagnosis or detection of patients at risk for developing osteoporosis. The novel knowledge generated in these studies will found the basis of new treatment modalities aiming at increasing bone formation rather than reducing bone resorption.
Acronym: OSTEOGENE Project number: LSHM-CT-2003-502941 EC contribution: 2 000 000 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/01/2004
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AGEACTION
Realising the potential of biological ageing research

Summary
AGEACTION aims to structure a process to: (i) develop a stronger sense of common purpose to deliver the knowledge base that will extend health, reduce dependency, and improve quality of life for Europes older people; (ii) identify the links between biological ageing research and the underpinning mechanisms of a very wide range of medical conditions (disability, frailty, disease) for which age is the single biggest risk factor; (iii) identify links between biological ageing research and social factors such as nutrition,education,lifestyle,housing,transport and culture that will help to exploit synergies that can lead to extended health, reduced dependency, and improved quality of life for older people; (iv) stimulate new interactions between biological ageing research and technological innovation that can lead to extended health, reduced dependency, and improved quality of life for older people; (v) stimulate closer engagement between biological ageing research and industry across a range of activities leading to creation of new business opportunities,particularly the formation of SMEs to exploit and develop Europes growing research capability in biological ageing research; (vi) create closer interactions between biological ageing research and those involved in financial planning in order to take better account of new insights into factors that affect life expectancy, health expectancy, and projected financial needs (including health and social support) for older people; (vii) provide for Europes older people (and younger people the future old) opportunities for greater awareness and more accurate reporting of advances in biological understanding of the ageing process that can lead to informed decision-making and empowerment to maximise opportunities for healthy old age; (viii) give Europes policymakers a clearer understanding of the nature of the ageing process and of the potential arising from the above activities. little effective linkage between other areas of activity (social, medical, economic, engineering) and biological ageing research, which aims to understand the nature of the ageing process itself what causes ageing, what can modify it, what underlies the continuing increases in life expectancy and declines in mortality of the oldest-old across Europe, and how biological ageing interacts with other factors that influence the lives of older people. This lack of interaction has resulted in a failure so far to exploit important linkages and to make the most of the enormous opportunities which exist to harness the growing understanding of the biological nature of the ageing process to help improve the health (understood in the WHO sense of complete mental, physical, and social well-being) and quality of life of Europes older people.The reasons for the present situation are easily understood. First, biological ageing research is relatively new and is itself still fragmented. Second, recent advances in biological ageing research have overturned many of the traditional conceptions about ageing, but awareness of this has yet to influence other spheres of activity.Third, no suitable action has yet taken place to bring together the various groups that need to engage with the difficult but essential task of building the necessary bridges between biological ageing research and other domains.
Aim
The main aim of the AGEACTION SSA is to structure a process culminating in a high-level conference that will provide a unique opportunity to realise the potential of biological ageing research in Europe, in the two senses of coming to awareness, and making something happen or real.Specifically,AGEACTION has the following objectives: 1.To set in motion a process that will enable biological ageing researchers to develop a stronger sense of common purpose and shared potential to deliver the knowledge base that will extend health, reduce dependency, and improve quality of life for Europes older people. 2.To set in motion a process that will identify the links between biological ageing research and the underpinning mechanisms of a very wide range of medical conditions (disability, frailty, disease) for which age is the single biggest risk factor. 3.To set in motion a process that will identify links between biological ageing research and social factors such as nutrition, education, lifestyle, housing, transport and culture that will help to exploit synergies that can lead to extended health, reduced dependency, and improved quality of life for older people. 4.To stimulate new interactions between biological ageing research and technological innovation, including information technology, nanotechnology and assistive technologies across a wide range that can lead to extended health, reduced dependency, and improved quality of life for older people.
Problem
Europe faces the immense challenge of unprecedented increase in life expectancy, which will continue into the 21st century.Although this state of affairs is the essentially positive outcome from multiple improvements in health care and socioeconomic circumstances, it nevertheless presents great strains for all member and associated states of the European Union in terms of increasing prevalence of age-related health problems and the growing financial implications for pensions, etc. It is widely recognised that in order to meet this challenge there needs to be multidisciplinary coordination of research and development effort. However, to date there has been
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5.To stimulate closer engagement between biological ageing research and industry across a range of activity including pharmaceuticals, nutraceuticals, diagnostics, nutrition, and lifestyle products leading to creation of new business opportunities and particularly the formation of SMEs to exploit and develop Europes growing research capability in biological ageing research. 6. To create closer interactions between biological ageing research and those involved in financial planning (actuaries, insurance companies, pension providers, etc) in order to take better account of new insights into factors that affect life expectancy, health expectancy,and projected financial needs (including health and social support) for older people. 7.To provide for Europes older people (and younger people the future old) opportunities for greater awareness and more accurate reporting of advances in biological understanding of the ageing process that can lead to informed decision-making and empowerment to maximise opportunities for healthy old age. 8.To provide for Europes policy-makers a clearer understanding of the nature of the ageing process and of the potential arising from these activities.
Coordinator
Prof. Kirkwood,Thomas B L University of Newcastle upon Tyne Henry Wellcome Laboratory for Biogerontology Institute for Ageing and Health Newcastle upon Tyne NE4 6BE, United Kingdom Phone: +44 191 256 3319 Fax: +44 191 256 3445 E-mail:Tom.Kirkwood@ncl.ac.uk Project web-site: To be developed Key words: ageing, longevity, health, age-related diseases, quality of life, interdisciplinary research, technology, genetics, nutrition.
Expected results
The main result will be the organisation of a high-level conference addressing the aims of the project. To achieve this result a number of enabling results will be required, including: (i) the establishment of relevant sector panels to define the agenda; (ii) the identification of venue, dates and participant lists; (iii) the preparation of background and supporting materials; (iv) the organisation of appropriate dissemination activities; (v) and the establishment and operation of procedures to maximise effective follow-through of the conference outputs.
Acronym: AGEACTION Project number: LSHM-CT-2005-512053 EC contribution: 170 000 Instrument: Specific Support Action Duration: 24 months Starting date: 01/11/2005
The project has a wide range of potential applications which are directly related to its aims.
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Cancer
INTACT BIOCARE Angiotargeting PRIMA Active p53 EMIL TRANSFOG FIRST CANCERDEGRADOME STROMA Mutp53 MOL CANCER MED EUROXY MAESTRO CCPRB eTUMOUR TRANSBIG European LeukaemiaNet DNA METHYLATION European MCL Network BRECOSM MetaBre ENACT PROTHETS P-MARK EUSTIR EUROCAN +PLUS 162 164 166 168 170 173 176 179 182 185 187 191 194 195 196 198 200 202 206 209 212 214 217 219 221 223 225
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Introduction
1st Call: FP6-2004-LIFESCIHEALTH

LSH-2002-2.2.0-1 Translating basic knowledge of functional oncogenomics into cancer diagnoses and treatment - INTACT - Active p53 - TRANSFOG 162 170 176 LSH-2002-2.2.0-3 Networking for treatment and/or prevention clinical trials (phase I and II) aimed at improving clinical practice in the light of new molecular knowledge - TRANSBIG - European LeukaemiaNet 200 202
LSH-2002-2.2.0-2 Multidisciplinary research to explore and validate molecular targets for innovative treatment - Angiotargeting - PRIMA - CANCERDEGRADOME - STROMA - Mutp53 - MOL CANCER MED - EUROXY 166 168 182 185 187 191 194
LSH-2002-2.2.0-4 Innovative research in radiation therapy - FIRST - MAESTRO 179 195
LSH-2002-2.2.0-5 Molecular imaging for early detection of tumours and monitoring of treatment - EMIL - eTUMOUR - BIOCARE 173 198 164
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3rd Call: FP6-2004-LIFESCIHEALTH-4

LSH-2002-2.2.0-6 Networking of quality controlled cancer registries and repositories for molecular epidemiology and quality assessment - CCPRB 196 LSH-2004-2.2.0-9: Feasibility Study for the coordination of national Cancer research activities. - EUSTIR - EUROCAN +PLUS 223 225
LSH-2002-2.2.0-7 Molecular mechanisms involved in organ-specific metastatic growth processes in breast cancer - BRECOSM - MetaBre 212 214
LSH-2002-2.2.0-8 Translational research on promising predictive and prognostic markers - DNA METHYLATION - European MCL Network - ENACT - PROTHETS - P-MARK 206 209 217 219 221
LSH-2002-2.2.0-9 Molecular mechanisms of cancer-related pain LSH-2002-2.2.0-10 Workshop on correlative laboratory studies relevant to therapeutic clinical studies
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INTACT
Identification of novel targets for cancer therapy

Summary
Despite intensive worldwide research efforts, cancer remains a devastating, often poorly treatable disease.We propose to develop and apply new functional genomics technologies that will provide unique approaches to the design of new pathway-specific cancer therapies.Our specific objectives are: 1. to develop large-scale functional genomic analysis to identify novel mechanisms involved in cancer development; specifically, we will generate the tools and technologies to carry out genome-wide lossof-function screens in mammalian cells. 2. to apply these technologies to specific models of major human cancercausing pathways to define novel targets for therapy. 3. to use existing and generate novel mouse models and non-invasive tumour imaging to validate and assay cancer gene function in vivo and to develop new treatment modalities. 4. to develop cell-based assays for cancer-relevant genes and pathways that will serve as readout for the identification of anticancer agents through the screening of chemical compound libraries. 5. to distribute and disseminate the novel technologies for the study of gene function in vitro and in vivo within the consortium and to researchers in the European Community. To reach these objectives we have formed a multidisciplinary research consortium, including top scientists with extensive experience in developing innovative genomics technologies and with an excellent track record in identifying key signaling molecules involved in cancer, as well as SMEs with experience in identifying cancer-relevant genes and in screening chemical compound libraries.The location of most of the partners at leading European cancer centres will ensure optimal conditions for the development of novel cancer-specific treatments. 2.To generate novel tools in the form of RNAi retroviral libraries (mouse and human), cell-based assays, mouse models and reagents that will be distributed on a non-profit cost-charge to academic researchers in the European Community. 3.To develop novel technologies for target validation in mouse and to develop mouse models to validate the role of the identified genes in the development of cancer. 4.To develop cell-based assays for cancer-relevant genes that will serve as a starting point for the identification of anticancer agents through the screening of chemical compound libraries.At the end of the four-year programme, collaboration with large pharmaceutical companies will lead to further refinement of leadcompounds and the possible introduction of novel anti-cancer agents into clinical trials. 5.To develop novel technologies to study gene function in vitro and vivo, and to distribute these technologies within the consortium and subsequently to researchers in the European Community. A. Schematic drawing of the pSUPER vector and the predicted stem-loop precursor transcript that is processed by intracellular RNases to siRNAlike molecules. B. Schematic drawing of a gene-specific pSUPER insert, consisting of two 59-mer oligonucleotides that contain a 19 nt gene-specific insert, a loop sequence, followed by the reverse-complement of the same 19 nt gene-specific insert and a termination signal (5xT).
Specific phases of the project

1. Establishment of the technology platforms: a. development of bar-code screen for the human siRNA library b. generation of mouse siRNA library c. development of protocols for high-efficient reverse infection of primary cells d. development of ERM-tag screen e. development of lentivirus vectors and protocols for making transgenic mice.
Scientific and technological objectives

1. Use large-scale functional genomics,in particular genome-wide lossof-function screens, to identify novel mechanisms, including novel oncogenes and tumour suppressor genes, involved in the development of human cancer.
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Coordinator
Prof. Helin, Kristian Biotech Research & Innovation Centre (BRIC) Fruebjergvej 3 2100 Copenhagen, Denmark Phone: + 45 39 17 96 66 Fax: + 45 39 17 96 69 E-mail: kristian.helin@bric.dk Project web-site: http://www.imt.uni-marburg.de/intact/ Key words: RNAI Libraries, Oncogenes,Tumour suppressors, Signaling, Mouse models, Compound medical libraries. Stable siRNA expression vector contains a gene specific identifier. Expression vectors for siRNAs encode a short hairpin RNA molecule (RNA hairpin) (Brummelkamp et al., 2002b).
Partners
Prof. Pelicci, Pier Giuseppe, European Institute of Oncology, Milan, Italy Berns, Anton , Cancer Institute, Amsterdam,The Netherlands Bernards, Ren, Cancer Institute, Amsterdam,The Netherlands Van Lohuizen, Maarten, Cancer Institute, Amsterdam,The Netherlands Blasco, Maria, Spanish National Cancer Center, Madrid, Spain Serrano, Manuel, Spanish National Cancer Center, Madrid, Spain Baccarini, Manuela, Vienna Biocenter, Vienna, Austria Schmitt, Clemens, Max-Delbrck-Center, Berlin, Germany Eilers, Martin, University of Marburg, Marburg, Germany Trumpp, Andreas, ISREC, Lausanne, Switzerland Auguet, Michel, ISREC, Lausanne Karen Vousden, Beatson, CR-UK, Glasgow, United Kingdom Dejean, Anne, Pasteur, Paris, France Morphochem, Munich, Germany Agendia, Amsterdam,The Netherlands
Acronym: INTACT Project number: LSHC-CT-2003-506803 EC contribution: 8 200 000 Instrument: Network of Excellence Duration: 48 months Starting date: 01/01/2004
2. Establishment of cellular models for performing ERM-tag and siRNA library screens. 3. Determination of cancer relevance of identified genes through assessment of their expression level in primary human tumors, characterisation of their biological function, and generation of mouse models. 4. Development of cell-based assays for newly identified cancer relevant genes for the use of screening of compound libraries.
Bar code screen. Schematic outline of bar code siRNA hybridisation screen to identify genes that increase cellular fitness after stress or decrease cellular fitness after stress.
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BIOCARE
Molecular imaging for biologically optimised cancer therapy

Summary
Early tumour detection and response monitoring require maximum sensitivity and specificity of the imaging method. During the 1970s and early 1980s, Computed Tomography (CT) with diagnostic X-rays made a revolution in accurate delineation of normal tissue anatomy as well as gross tumour growth. In the mid 1980s and 1990s, magnetic resonance imaging and spectroscopy allowed even more accurate differential diagnostics of soft tissue malignancies with the possibility of distinguishing between tumour tissues,oedema and normal tissues. The integration of positron emission and X-Ray computed tomography in one unit is bringing another diagnostic revolution to tumour imaging. By combining these two imaging modalities, an unprecedented accuracy in the delineation of the tumour on a background of normal tissue anatomy is achieved. Although significant progress in cancer cure rates have been achieved in the past,approximately 45% of patients still succumb to their disease due to local (~25%) and/or distant (2025%) tumour recurrence. Early detection of small tumour deposits may allow successful treatment. Moreover, lack of individualised tumour characteristics leads to erroneous over - and under-treatment and precludes individualised therapy selection. Molecular tumour imaging is an active area of development and may provide a non-invasive tool to tackle some of these problems as it has benefited substantially from the recent development of our knowledge about molecular genomics and proteomics pathways. The development is very rapid and many new approaches are likely to be developed in the coming years. The most commonly used radiotracer used; fluorodeoxyglucose (FDG), is not tumour-specific, as all regions with an increased metabolic rate will show an elevated glucose uptake. More specific tumour markers allowing an even more accurate imaging of the tumour clonogen density are therefore of importance as they may image e.g. perfusion, hypoxia, amino acid and receptor status. Methionine and other amino acids are already available as tracers and, although they may be better than FDG, they may still not be sufficiently specific, since they are incorporated in all tissues that are being renewed. For some tumours, there are more specific markers such as 11C-Choline, and FHBC or FDHT (Fluorodihydrotestosterone) for imaging androgen receptors in prostate cancer. Vasculature could be visualised by known tracers such as ammonia (
11CH 3)
Project objective
BioCare is focused on developing new techniques and approaches to increase the sensitivity and specificity of existing tumour imaging techniques as well as introducing more systematic and adaptive approaches based on high-quality tumour imaging. The objective of the project is to: improve and speed up the implementation of PET-CT imaging in cancer management develop new European intellectual property to improve tumour imaging by more specific tumour tracers. They will result in considerably increased resolution, sensitivity and specificity in tumour detection. BioCare is subdivided into four major activities addressed through nine work packages.The areas are namely: PET camera development, development of new tracers, experimental and clinical validation and implementation of the techniques above in medical oncology. Work package 1 Design of detectors for whole body PET systems with a high intrinsic resolution. Investigation of the possibility of integrating a PET-CT device with a radiation therapy unit with an ergonomic design both for patients and personnel to simulate imaging of the tumour response and responsiveness as well as dose delivery in vivo. Work package 2 Methods for real-time monitoring of the apoptotic response to radio therapy and to predict early responses during the course of therapy for optimising therapy planning and making prognostic evaluations. Work package 3 To promote understanding of the complex processes induced by cancer therapy, especially radiation therapy, through a comprehensive evaluation of established (e.g. FDG, FLT) and new tracers for therapy response assessment in human tumour models. Work package 4 Development of radiolabelled aptamers, small tailor-made oligonucleotides aimed at tumour-specific target structures for individually optimised cancer treatment. Work package 5 Development of molecular imaging methods that can vissualize and quantify temporal and spatial changes in hypoxia in human tumours. Work package 6 To investigate the use of state-of-the-art Positron Emission Tomography with Molecular Imaging and X-Ray CT-based anatomical imaging to monitor the radio- and chemotherapy of cancer and to trace the early response of the tumour of interest by quantifying the sensitivity of the tumour in three dimensions in vivo.
or water (H215O).
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Work packages 7 & 9 PET-CT-SIM molecular tumour imaging and treatment simulation with conformal RT to make the concept of a biological target volume reality leading to biologically optimised molecular tumour imaging and radiation treatment planning. Work package 8 To examine molecular targets involved in tumour angiogenesis using anti--angiogenetic probes and to investigate the value of functionrelated indices of response (e.g. blood volume, flow, permeability, metabolism, etc.) to non--invasively monitor the effects of therapy.
Coordinator
Prof. Brahme,Anders Department of Medical Radiation Physics Karolinska Institutet 171 77 Stockholm, Sweden Phone: + 46 8 517 724 96 E-mail: anders.brahme@radfys.ki.se Key words: Tumour imaging, PET, PET-CT, MRSI, Optic tumour imaging,Tumour response monitoring.
Partners
Dresden University of Technology, Germany The Victoria University of Manchester; United Kingdom Forschungszentrum Rossendorf e.V., Germany University of Maastricht, The Netherlands Katholieke Stichting UMC St. Radboud,The Netherlands Aarhus University Hospital, Denmark Institut Gustave-Roussy, France Universitt Hamburg, Germany Universit Catholique de Louvain, Belgium Universitair Ziekenhuis Gasthuisberg, Belgium The Netherlands Cancer Institute,The Netherlands Soltan Institute for Nuclear Studies, Poland University of Turku, Finland PencilBeam Technologies AB, Sweden PEVIVA AB, Sweden RayClinic AB, Sweden European Society for Therapeutic Radiology and Oncology, Belgium European Organization for Nuclear Research, Switzerland RayTherapy Imaging AB, Sweden RaySearch MedicalAB, Sweden
Acronym: BIOCARE Project number: LSHC-CT-2004-505785 EC contribution: 6 000 000 Instrument: Integrated Project Duration: 54 months Starting date: 01/03/04
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Angiotargeting
Multidisciplinary research to explore and validate molecular targets for innovative treatments
Summary
Solid tumour growth depends on a continuous supply of nutrients by new blood vessels that grow into the tumour. This process, termed tumour angiogenesis, is regulated by a number of complex factors involving both tumour and host cells. How the tumours communicate with the normal cells to produce blood vessels has during the last years gained increasing attention and it has recently been shown that targeting the host vasculature has a therapeutic potential for certain tumours. The Integrated Project Angiotargeting focuses on the identification of novel genes and gene products that regulate tumour angiogenesis and on validating such products as therapeutic targets. In addition, novel therapeutic strategies will be evaluated in preclinical models as well as in the clinic.Angiotargeting will therefore open new avenues in the search for new therapeutic compounds towards malignant disease. Angiotargeting focus on the identification and validation of novel therapeutic targets on tumour blood vessels. Such targets will be used in the development of novel therapeutic strategies towards tumour blood vessels growth. The concept of treating genetically stable vascular cells, rather than drifting tumour cells, has gained increasing acceptance in the scientific community. It is essential that European research centres co-ordinate their research efforts within this promising area of science and that innovations within the field of angiogenesis are supported at European level.The Angiotargeting consortium is contributing particularly to the knowledge base for the development of the European biotechnology industry within the field of angiogenesis. Angiotargeting represents an added value on a range of aspects related to integration of research in Europe by combining some of the most qualified research groups and establishing a European-based strategy for treatment of cancer targeting the tumour vascular supply. Angiotargeting combines front-line knowledge of basic and clinical research involving global gene and protein analyses, stem cell research, physiological mechanisms, advanced animal model systems, molecular imaging and clinical research. The consortium exploits the research expertise accumulated at six European universities,six European research institutions and two biotechnology companies with a common goal of finding new therapeutic targets,that cannot be achieved at national level.
Scientific objectives
1.To co-ordinate multidisciplinary research and basic knowledge within the field of tumour cell matrix interactions, to provide the basis for novel therapeutic strategies against tumour progression. 2.To get a comprehensive understanding of how tumours generate vascular supply by using advanced genetic model systems. 3.To forward new technological approaches, including high throughput screening technologies within the field of tumour cellmatrix interactions,to define and validate key molecular targets that control tumour angiogenesis. 4.To assess and validate strategies that disrupt and abrogate tumour angiogenesis and invasion.This includes the validation of novel as well as described potential therapeutic targets towards the tumour vascular and invasive transcriptome and proteome. 5.To establish comprehensive bioinformatics tools for the analysis of high throughput gene and protein data,from defined cell populations within tumours, with the aim of validating targets by assessing therapeutic efficacy in preclinical as well as clinical models. 6.To implement state of the art platforms for preclinical and clinical assessment of newly developed compounds.
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Coordinator
Prof. Bjerkvig, Rolf University of Bergen Musplass 1 5020 Bergen, Norway Phone: + 47 55 58 63 52 Fax: +47 55 58 63 60 E-mail: rolf.bjerkvig@pki.uib.no Key words: Tumour Targetting, Angiogenesis
Partners
University of Bergen, Norway European Institute of Oncology, Milan, Italy University of Uppsala, Sweden Netherlands Cancer Institute,The Netherlands Xantos Biomedicine AG, Germany Maastricht University,The Netherlands University of Oxford, United Kingdom Vrije Universiteit Medical Centre, Amsterdam, The Netherlands University of Oulu, Finland Institute of Experimental Medicine, Academy of Sciences of the Czech Republic Centre Recherche de Public Sant, Luxembourg The Karolinska Institute, Sweden
Acronym: Angiotargeting Project number: LSHC-CT-2004-504743 EC contribution: 6 000 000 Instrument: Integrated Project Duration: 48 months Starting date: 01/11/2004
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PRIMA
Summary
Prostate cancer is one of the most common malignancies in the western male population. In Europe, approximately 40 000 men die of prostate cancer each year and that number is likely to increase, due to the ageing population,to roughly 60 000 men in 2020.Therefore prostate cancer is a significant medical problem with which the European Community will be confronted increasingly in the oncoming decades. For localised prostate cancer, radical therapies aiming at eradicating all malignant processes in the prostate gland are available that can cure the patient.However,if the malignant process has locally or distantly spread, no curative medical intervention is currently available. Since the early 1940s androgen ablation therapy has been the mainstay in an attempt to control prostate neoplasms, but unfortunately this is only of a palliative nature and tumour progression due to the expansive growth of cancer cells that are unresponsive to currently available hormone therapies is inevitable. Furthermore, prostate cancer cells have a strong tendency to spread to the bone, a site where metastases cause great morbidity, ultimately leading to a painful death.
therapy-unresponsive bone metastatic disease will use functional genomics and expression profiling as technology platforms.These technology platforms will also be used to identify novel candidate targets for treatment. A specific bioinformatics platform will be developed to analyse all collected data. In the targeted discovery phase, a great number of candidate target genes will be identified that, in addition to already available targets from earlier collaborative programmes, need to be phenotypically and/or functionally validated. Phenotypical validation will be performed in archival material of patients with a well documented follow-up, in all stages of the disease process. In addition, high-throughput functional, cell-based analysis and molecular target validation will be performed by knocking down genes that are over-expressed in hormone refractory or metastatic prostate cancers using RNA interference.The knowledge obtained from the targeted discovery phase and validation phase will be used to establish assays which will in turn be used for high throughput screening of low molecular weight compounds (i.e., more than 25 000 compounds).The assays will use easy-to-upscale formats and reporters that can be easily read out. The final phase of the project will be the testing of interesting compounds for their ability to efficiently interfere with cancer cell proliferation and/or survival in a bone environment in the absence of androgens.The lead compounds will be tested for their efficacy in models for bone metastatic prostate cancer. Hence translation of the obtained knowledge into therapeutic strategies is an integrated part of the project.
Research plan
In the PRIMA project a multidisciplinary effort is proposed to explore the pathways that lead to the most lethal aspect of prostate cancer, i.e., hormone-therapy-unresponsive bone metastatic lesions. It has become clear that in the majority of advanced prostate cancers the androgen receptor signalling pathway is active even in the absence of androgens. European research teams with a leading role in androgen receptor research will integrate their efforts to exploit androgen receptor mediated signaling as a therapeutic target. This should be achieved by: 1) targeting the androgen receptor itself; 2) interfering with androgen receptor activation by non-steroids; 3) studying non-transcriptional functions of the androgen receptor; 4) targeting essential androgen receptor co-factors over-expressed in prostate cancer; and 5) inhibiting those androgen receptor target genes which regulate prostate cancer cell growth, survival and differentiation.The androgen receptor teams will join forces with European investigators that study the interaction between prostate cancer cells and the bone microenvironment. Expression profiling of members of the TGF- super family and signal transduction molecules in cell lines, animal models and clinical specimens should provide more insight in the role of these molecules in the development of bone metastatic lesions. Furthermore, epithelium-mesenchymal transition will be extensively studied. The exploration of the pathways leading to hormone-
Consortium
The PRIMA consortium is organised in a kind of matrix structure, in which the top European research laboratories in the field of urological oncological research, particularly prostate cancer, have joined forces with strong disciplinary teams in the field of molecular life sciences. The experimental urology laboratories have the advantage of covering the distance from the clinical need to the experimental research approach and vice versa. Research plans are aimed at clinical questions, in the case of this project the treatment of hormone unresponsive prostate cancer.The clinical applicabilitydriven research efforts of these typical experimental urology research teams does not allow in-depth investment in platform technologies, such as genomics, transcriptomics and bio-informatics. Therefore, the efforts are integrated with expert European teams in molecular endocrinology, bioinformatics, functional genomics, expression profiling and design and establishment of (screening) models. This has resulted in an integrated consortium aimed at solving a major clinical issue, i.e., an effective treatment for prostate cancer.
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Related projects
Currently, two other FP6-projects dealing with prostate cancer are in contract negotiation phase for funding by the EC.The project PMARK, a STREP, concentrates on the identification and development of new prognostic markers for prostate cancer, and GIANT, an IP, aims at the development of viral and non-viral vectors for the targeted treatment of prostate cancer. The three consortia are closely related and have many existing collaborations. In order to adequately inform scientists and urologists about the knowledge generated by the projects and to get as many clinicians as possible involved in the projects, a team of six urologists and scientists is responsible for external communication and representation of the three consortia.This team includes the three coordinators as well as people involved in at least two of the projects. Integrated efforts will be made to inform, educate and discuss the progress of the projects with the European Urology community through the European Association of Urology (EAU).
Coordinator
Prof. Schalken, J A University Medical Centre St. Radboud Dept. of Experimental Urology PO Box 9101 6500 HB Nijmegen,The Netherlands Phone: + 31 24 361 4146 Fax: + 31 24 354 1222 E-mail: primaproject@uro.umcn.nl Project web-site: www.primaproject.org Key words: Prostate Cancer, Androgen Receptor, Bone Metastasis
Partners
Erasmus Medical Center Rotterdam,The Netherlands Centre Eurpen de Recherche en Biologie et Mdecine, France University of Sheffield, United Kingdom Turun Yliopisto, Finland Speciality Chemical Services Holding B.V.,The Netherlands Medizin Universitaet Innsbruck,Austria University of New Castle upon Tyne, United Kingdom Forschungszentrum Karlsruhe GMBH, Germany Universitaet Bern, Switzerland University of York, United Kingdom Centre de Recherche pour les pathologies prostatiques, France Leiden University Medical Centre,The Netherlands University of Tampere, Finand Weizmann Institute of Science, Israel The Chancellor , Master and Scholars of the University of Cambridge, United Kingdom
Acronym: PRIMA Project number: LSHC-CT-2004-504587 EC contribution: 6 000 000 Instrument: Integrated Project Duration: 60 months Starting date: 01/07/2004
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Active p53
Manipulating tumour suppression: a key to improve cancer treatment

Summary
The prevention of human cancer development depends on the integrity of a complex network of defence mechanisms that help cells to respond to various stress conditions. A key player in this network is the p53 tumour suppressor protein. By inducing efficient growth inhibition, p53 eliminates cancer cells thereby preventing the development of human malignancies.These functions of p53 often determine the efficacy of anti-cancer therapies. Although p53 is frequently mutated in some cancers, in about 50% of all human cancers p53 is non-mutated and could,in principle,be activated to prevent tumour progression.This situation is prevalent among a wide range of cancers, notably breast carcinoma. However, p53 activity is hampered by malfunction of its many modulators, such as Mdm2 or p73, which govern p53 tumour suppressive activity by acting upstream and/or downstream of p53. There is therefore a crucial need to understand how p53 modulators contribute to human malignancies. Based on this information, we propose to develop rational therapeutic approaches to manipulate p53 modulators, thereby wakening the sleeping tumour suppression activities of p53, allowing it to eliminate cancer cells.A carefully structured consortium comprises 19 academic research centres and SMEs (see diagram). It will interactively build a technology platform to comparatively identify,characterise and evaluate the regulatory roles of p53 modulators and define the mechanisms of their action. Large-scale gene functional analyses will be conducted to identify relevant signalling pathways that impair or mediate tumour suppression by p53. These analyses will include p53 activators and inhibitors,p53 homologues p73/p63,and dissection of p53 target genes mediating apoptosis and growth arrest. Our links with highly profiled clinical partners and our access to large,well-characterised and clinically documented sample collections will enable the evaluation of diagnostic expression profiles, and their potential prognosis value in cancer. Particular emphasis will be directed towards translating the information on p53 regulation into the development of new anti-cancer therapies. p53 regulatory proteins will be used for the identification of new molecular targets for drug discovery. Outline of the consortium
Problem
Cancer is the second leading cause of death in European countries, and one of the most imminent health problems in the developed world. The p53 protein is generally recognized as the key determinant of tumour suppression. It has been declared by the European Union that a large co-operative effort is needed to ensure that every European citizen will rapidly profit from the revolution of knowledge in cancer management (Philippe Busquin). The presence of wild type p53 is particularly prevalent in breast cancer, the type of cancer that stands at the centre of the European cancer policy.Since breast cancer affects mostly (though not exclusively) women, breast cancer research is also an important task to implement the gender dimension into basic research. For these reasons, we will choose breast cancer as one of our focuses in this block of work.Moreover,a non-mutated but inactive p53 is also found in a high percentage of the most frequent intracranial tumour of children, neuroblastoma. Since paediatric tumours are particularly dramatic events for patients and their families, it appears appropriate to put another focus on this tumour species.
Aim
The principal aim of this proposal is to ease both diagnosis and prognostic classification, as well as the efforts towards novel therapy regimens to treat patients suffering from breast cancer and neuroblastoma. Overall, the integrated action of our consortium is aiming at re-establishing tumour suppressor activity in cancer, thereby translating basic knowledge of functional oncogenomics into cancer diagnoses and treatment, and contributing to leadership in European health technology.
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Expected results
The overall goals of this integrated effort are to understand: 1. which modulators determine the tumour-suppressive activities of the p53 family members 2. by what mechanisms these modulators affect the tumour suppression activities 3. how the expression and activity of p53 modulators is regulated 4. whether p53 modulators affect the biological characteristics of tumour cells 5. whether the status of p53 modulators correlates with the clinical outcome and can be used to determine the individual prognosis 6. whether and how p53 modulators can be targeted by therapeutic strategies, and be manipulated towards regaining tumour suppression. 7. disseminate the knowledge that will be produced to practically all the interested parties including medical doctors,and managerial staff in the industries 8. familiarise SMEs with scientific research work and state-of-the-art technology that will provide the necessary know-how for the improvement of their services and competitiveness. The four blocks are linked as outlined.These links are formed according to the biological activities governing p53, and therefore, the scheme simultaneously depicts biological dependencies as well as the mode of collaboration within the consortium. Activators of p53 frequently act by antagonizing p53 inhibitors, and vice versa, this will be taken into account by networking accordingly between the blocks 1 and 2. Activators and inhibitors of p53 may act on p73 and p63 as well, and this was shown to be true in a number of cases.Therefore, each regulator of p53 will be assessed regarding its impact on p53-homologues as well, by collaborative efforts between Block of work 3 with blocks 1 and 2. Finally, the assessment of p53 downstream activities, and the development of cutting-edge technologies to analyze them, will be used throughout the consortium.Therefore, Block of work 4 forms a basis not only to reach excellence on its own, but also to effectively advance the progress of blocks 1, 2 and 3
The ultimate general objective of this research proposal is to provide a basis for the re-activation of tumour suppression and the design of novel therapeutic approaches to combat cancer. In particular, we are aiming at modulating p53 family activities to decrease resistance of tumour cells to anti-cancer treatments.Thus, the ultimate goal of this research proposal is the identification of novel drug targets and strategies for induction of p53-mediated apoptosis in therapy-resistant cancer cells. The participation of the SMEs is expected to play a key role to the practical application of the knowledge that will be produced.
The members of our consortium have identified a number of p53-modulators (stage 1), and in some cases, have begun to understand their mechanisms of action.We are now pursuing an integrated strategy to advance our knowledge on the nature of these modulators through stages 2-5, and ultimately to evaluate their potential as candidate drug targets (stage 6).We are starting from the scenario outlined below.
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Coordinator
Dr Blandino, Giovanni Department of Experimental Oncology Regina Elena Cancer Institute Via delle Messi DOro 156 Rome, Italy Phone: + 39 06 52662522 Fax: + 39 06 52662505 E-mail: blandino@ifo.it Project web-site: http://www.europeire.it/Activep53/intro.html Key words: tumour suppression, p53, p73, p63, inhibitors, activators, technology Dr Bartk, Jiry Danish Cancer Society Dept. of Cell Cycle and Cancer Institute of Cancer Biology Danish Cancer Society Copenhagen, Denmark Dr Levrero, Massimo Fondazione Andrea Cesalpino Laboratory of Gene Expression Rome, Italy Dr Jochemsen, Aart Gerrit Dept. Molecular and Cell Biology,Tumour Suppressor Group Leiden University Medical Center Leiden,The Netherlands Dr Selivanova, Galina Karolinska Institute Department of Laboratory Medicine, Stokholm, Sweden Dr Del Sal, Giannino Universit Degli Studi Di Trieste Dipartimento di Biochimica Biofisica E Chimica Delle Macromolecole Trieste, Italy Dr Iggo, Richard Swiss Institute for Experimental Cancer Research Oncogene Group Dr Deppert,Wolfgang Heinrich-Pette-Institut fr Experimentelle Virologie und Immunolgie an der Universitt Hamburg Department of Tumour Virology Hamburg, Germany Dr Lane, David University of Dundee Department of Surgery and Molecular Oncology Nethergate, Dundee, United Kingdom Biotecgen s.r.l. Department of Biological Sciences Institute of Physiology Lecce, Italy Dr Moarefi, Ismail SiREEN AG Martinsried, Germany
Partners
Dr Dobbelstein, Matthias Centre of Medical Biotechnology University of Southern Denmark Odense Denmark Dr Haupt,Ygal The Lautenberg Center for General and Tumour Immunology The Hebrew University - Hadassah Medical School, Jeruslem, Israel Dr Kroemer, Guido Centre National de la Recherche Scientifique Laboratoire de Gntique Oncologique UMR8125 Institut Gustave Roussy Villejuif, France Dr Lu, Xin Ludwig Institut Fur Krebforschung Tumour Suppressor Group Ludwig Institute For Cancer Research London, United Kingdom Dr Voudsen, Karen The Beatson Institute For Cancer Research Tumour Suppressor Laboratory, Glasgow, United Kingdom Dr Rotter,Varda Weizmann Institute of Science Molecular Cell Biology / Biology Rehovot, Israel Dr La Thangue, Nicholas B University of Glasgow Biochemistry and Molecular Biology Institute of Biomedical and Life Sciences, Cathcart Lab Glasgow, United Kingdom Dr Melino, Gerry Medical Research Council Leicester, United Kingdom
Acronym: Active p53 Project number: LSHC-CT-2004-503576 EC contribution: 6 000 000 Instrument: Integrated Project Duration: 60 months Starting date: 01/12/2004
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Molecular imaging of cancer

Summary
The general objective of the EMIL Network of Excellence is to merge the leading European research teams in molecular imaging, in universities, research centres and small and medium enterprises, to focus on early diagnosis, prognosis and therapeutic evaluation of cancer. The EMIL network brings together 58 partners representing 43 bodies in 13 European countries, and integrates six technological facilities: Orsay (France), Turin (Italy), Cologne (Germany), Leiden (Netherlands), Milan (Italy) and Antwerp (Belgium) around a common activity programme including: integration activities: creation of a network of technological and training facilities favouring the mobility of researchers and the integration of small and medium sized enterprises into the EMIL network dissemination of expertise activities: training, communication, common knowledge management and intellectual property rights research activities:a common research programme with a horizontal dimension, making use of methodological tools of physics, biology and chemistry necessary for the further development of molecular imaging (instrument techniques, molecular probes, biological engineering), and a vertical integrative dimension, bringing together cancer imaging applications (early diagnostic imaging, development of new therapies, imaging for drug development). sample during analysis and are not applicable to whole body and longitudinal explorations. Hence they fail to recognise the essential character of cancer, development across time and space. On the other hand, in vivo imaging is a repeatable and non-invasive localisation technology with the potential to become the preferred means for cancer diagnostics and follow-up. However, imaging is based on evidencing a contrast between cancer and normal tissue, and this is quite challenging to perform in vivo in view of the fact that cancer cells are a clone of normal cells. Even though anatomic imaging can occur in vivo at sub-millimetre resolution, imaging techniques based on gross physical differences such as density or water content perform poorly in producing a contrast which must be based on specific imaging agents targeting tumour cells. Molecular imaging is a new science bridging together molecular biology and in vivo imaging with the aim to detect the expression of specific genes. Imaging science has made sufficient progress in the last decade to bridge the gap between physiology and molecular biology, and is now at the stage where it can perform molecular imaging of gene expression in vivo. Significant advances have occurred in molecular imaging modalities, including the nuclear medicine techniques of SPECT and PET, MRI and spectroscopy which have attained resolution sufficient for small animal imaging, and optical imaging, which can now reach unprecedented sensitivities.
Aim
The potential of molecular imaging is considerable. In fundamental research, it allows the visualisation of cell function and molecular processes in living organisms, in particular the monitoring of the stages of growth and ageing, the response to environmental factors, the exploration of cell movements, etc. In experimental medicine it identifies the molecular determinants of pathological processes in situ, evaluates new molecular therapies such as gene therapy, and accelerates drug development (delivery of active compounds, efficacy of vectors, etc.). With the evolution of imaging techniques and the capacity to transfer animal data directly into clinical applications, molecular imaging is a most promising technique to tackle cancer detection, following the rule of the three Ps: Precocious, Precise and Predictive. - Precocious: several successive mutations are necessary to make a cell cancerous. By detecting genetic anomalies at the very first mutation, molecular imaging could permit early diagnosis and prompt intervention right at the start of the cancer-forming process. - Precise: molecular imaging makes it possible to detect precisely, in space and time, the gene or genes that are dis-regulated in the cancer cell. The tumour can then be characterised with all the required molecular precision.
Problem
Cancer is characterised by an uncontrolled proliferation of cells that escape the rules of the organism they originate from. For normal cells, these rules are both spatial (a cells location is defined by its integration in an organised tissue) and temporal (a cell obeys the laws of controlled division and death corresponding to its programmed life cycle). Cancer cells disobey the laws of time and space, proliferate and invade. The last two decades have witnessed enormous advances in our understanding of cancer at molecular level and have demonstrated that it results from abnormal gene expression in cell clones. Gene expression analysis techniques are now witnessing systematic compilation of molecular data that can be used to provide accurate diagnosis and prognosis.These techniques are well-established and widely applied to in vitro biological samples, but they destroy the
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- Predictive: the fineness of the information obtained by molecular imaging makes it possible not only to determine the tumour type, but also to predict its evolution, adapt the treatment and monitor its efficacy. This is essential to: validate in the context of living organisms the targets and drugs designed by genome data mining and in vitro gene expression analysis through methods that are both non-invasive and repeatable acquire fundamental knowledge about the patterns of gene expression in normal tissues and define the changes in specific gene expression in cancer design and develop drugs targeting cancer-related gene expression allow precise evaluation of new treatments and new anticancer drugs that are required for progress in cancer management, through reliable measures of the cancer burden.
imaging, (ii) directly study alteration of gene expression, tumour cell proliferation and migration in vivo over an extended period of time in the same animal 7. to identify in vivo molecular targets of cancer and metastasis enabling an early diagnosis, assessment of disease progression and response to therapy 8. to establish imaging-guided patient-tailored therapies 9. to develop imaging technologies for in vivo drug screening using animal models predictive for human disease and applications to human clinical trials 10. to do molecular imaging of apoptosis in cancer.
1.Tumour diagnosis 2. Follow up of tumour progression
Expected results
The present initiative is taken to capitalise on the extraordinary opportunity for studying non-invasively gene expression and function in cancer, due to recent advances in molecular imaging modalities. Because molecular imaging is fundamentally multidisciplinary by nature, the instrument for this goal is a Network of Excellence bringing together genome-oriented scientists with the various actors of imaging science and the clinicians dedicated to formulating novel diagnostic methods based on imaging.The general objectives of EMIL are to: 1. coordinate the current effort in EMIL by merging 43 groups from universities, research centres and SMEs coming from different scientific and technical fields into one virtual excellence centre with dedicated technological training platforms and integrated dissemination and management activities 2. advance EMIL to the scientific, technical and economical status that should be expected from its value for European citizens, in order to improve cancer diagnosis follow-up, to promote and assist in the development of new targeted therapies, and translate science and technology progress into economical benefits 3. act as leverage for a strong technological development that can be fuelled through specific research and development projects. And more precisely: 4. to optimise hardware and software technologies for the integration of radiotracer, magnetic resonance and optical imaging data. This will require specific instrumental development and validation for cancer research, as well as software tools for the co-registration, quantitation and processing of multimodal data 5. to develop so called smart imaging probes which are specific for a given molecular process and which can be detected and localised by at least one imaging modality 6. to use further developments of mouse models of human cancer to: (i) improve the early detection of small cancers by advanced
3.Therapeutic evaluation
Coordinator
Tavitian, Bertrand CEA - SHFJ Unit dimagerie in vivo de lexpression des gnes 4 place du Gnral Leclerc 91401 Orsay, France E-mail:Tavitian@shfj.cea.fr Project web-site: www.emilnet.org Key words: EMIL, molecular imaging, cancer, drug development, guided therapies, tumour diagnosis, in vivo imaging of gene expression
Partners
Dipartimento di Chimica I.F.M., Universit degli di Studi di Torino,Turin, Italy Dept. of Neurology, Lab for Gene Therapy and Molecular Imaging, Klinikum at the University of Cologne (MEK), Germany Department of Endocrinology and Metabolic Diseases, Leiden University Medical Centre, The Netherlands Centre of Excellence on Neurodegenerative Diseases, Universit degli Studi di Milano, Milan, Italy Biospace Mesures, Paris, France Department of Biomedical Sciences and Dept Physics RUCA - Bio-Imaging Lab, Universiteit Antwerpen, Belgium
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MPI for Neurological Research, MRI Laboratory, Max Planck Society, Cologne, Germany CNRS- ICSN, Gif sur Yvette, France INSERM,ADR de Lyon, France Dept. of Medical Biochemistry and Genetics,The Panum Institute, University of Copenhagen, Faculty of Health, Denmark Department of Biological Chemistry, Group of Oligonucleotides, IOCB-AS of the Czech Republic Lab. of Oncogene Regulation, Institute of CarcinoGenesis, Moscow, Russian Federation Dept. of Organic Chemistry - NMR Laboratory, University of Mons-Hainaut, Belgium Laboratory de Mthodologie RMN, Fac des Sciences, Universit Henri Poincar, Nancy, France Facult des Sciences de Base (FSB), Institut de Chimie Molculaire et Biologique (ICMB) LCIB, Ecole Polytechnique Fdrale de Lausanne, Switzerland Department of Radiopathology & Medical Isotope Use, NCPH-National "FJC" Research Institute for Radiobiology & Radiohygiene, Budapest, Hungary Institute of Nuclear Chemistry, University of Mainz, Germany Coordination & Radiochemistry, Universit de Lige, Belgium Laboratory of Bioinorganic Chemistry & Biomedical NMR, Department of Biochemistry, Centro de Neurocincias de Coimbra e Biologia Celular, Coimbra, Portugal BRACCO Imaging S.P.A., Milan, Italy Radiology & Radiological Chemistry Division, University of Basel, Switzerland Consiglio Nazionale delle Ricerche, Istituto di Biostrutture e Bioimmagini, Naples, Italy Department of Inorganic Chemistry, Prague, Czech Republic Chemistry Laboratory, Durham University, United Kingdom Laboratory of Applied Organic Chemistry and Catalysis, Technische Universiteit Delft, The Netherlands Dept. of Inorganic and Analytical Chemistry, Laboratory of Rare Earths, University of Debrecen, Hungary Radiopharmaceutical Chemistry Laboratory, Deutsches KrebsForschungsZentrum Heidelberg, Germany SKYSCAN, Aartselaar, Belgium Mauna Kea Technologies, Paris, France
MR Solution Ltd, Guildford, United Kingdom Wolfson Molecular Imaging Centre,Academic Dept of Radiation Oncology,The Victoria University of Manchester, United Kingdom Gastroenterology Department, Hospital Clinic Provincial de Barcelona, Spain Department of Dermatology and Rudolf-Virchow, Centre for Experimental Biomedicine, Julius-Maximilians-Universitt Wrzburg, Germany Dept. of Radiology, Stichting Katholieke Universiteit, University Medical Centre Nijmegen, The Netherlands Department Ingenieria Electronica / E.T.S.I. Telecomunication, Universidad Politcnica de Madrid, Spain Department of Urology & Department of Clinical Research, Faculty of Medicine, University of Bern, Switzerland Department of Physics "E. Fermi", University of Pisa, Italy ForschungsZentrum Juelich GmbH, Zentrallabor fur Elektronik (ZEL), Juelich, Germany Department of Biochemistry, University of Cambridge, United Kingdom Centro Ciclotrone PET, Fondazione Centro San Raffaele del Monte Tabor, Milan, Italy Medres Medical Research GmbH iGR, Cologne, Germany Department of Nuclear Medicine, Radiochemistry & Radiopharmaceutical,Technical University, Munich, Germany
Acronym: EMIL Project number: LSHC-CT-2004-503569 EC contribution: 5 800 000 Instrument: Network of Excellence Duration: 60 months Starting date: 01/07/2004
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TRANSFOG
Translational and functional onco-genomics: from cancer-oriented genomic screenings to new diagnostic tools and improved cancer treatment
Summary
The TRANSFOG project aims at the systematic identification and functional characterization of novel cancer genes with high potential diagnostic and therapeutic value in breast, colon and lung cancer. The TRANSFOG partners will bring together world recognised competences and resources to reach the following, integrated research objectives: V. Establishment of a shared bioinformatic platform for functional oncoI. Identification of novel cancer-related genes of high clinicaldiagnostic potential, with a specific focus on progression and metastasis of colon, breast, lung cancer.This will be achieved mainly through extensive gene expression profiling of tumour/metastasis samples and of cell-based models of cancer progression.To extend the exploration range, differential proteomics and epigenetic analysis are also planned. The foreseen outcome is a ranked list of novel candidate cancer genes emerging from integration of the screening results, that will undergo functional characterisation and/or diagnostic validation. II. Set-up of technologies for systematic cancer gene functional analysis and for identification of new molecular targets. Gene functional analysis will be enabled by assembling collections of fulllength cDNAs (FL-cDNAs) and of short interfering RNAs (siRNAs) subcloned in expression plasmids, to assess the consequences of gene gain-or loss-of-function in cell-based and preclinical models. III. Systematic exploration of oncogenic/antioncogenic signalling pathways, epigenetic regulatory mechanisms.Taking advantage of the FL-cDNA and siRNA collections made available by the project, cellbased experimental systems to study protein-protein interaction, reporter gene expression and epigenetic modifications will be exploited for systematic analysis of the candidate genes. This will result in datasets of protein-protein interaction, transcriptional and epigenetic regulation allowing a comprehensive overview of the alterations in signalling and regulatory networks involved in cancer progression. The TRANSFOG project will deliver a consistent and integrated amount of functional data on genes of as yet unknown activity and biological role. In the process of reaching this objective, the participating units will be enabled to set up truly post-genomic efforts toward systematic gene functional characterisation.New technologies will be developed that will allow exploration of gene regulatory networks,protein-protein interactions and high-throughput cell-based evaluation of basic biological functions such as motility, growth, apoptosis, invasion, adhesion, polarisation and more complex processes as in vitro epithelial morphogenesis and angiogenesis.The technologies for systematic gene functional characterisation developed here will be useful for functional studies involving a variety of physiological and pathological processes, and will be made available to the scientific community in the frame of a collaborative research network.The bioinformatic networking endowed with the project will enable participating units to share tools for data handling, database exploration and functional gene annotation. It will also facilitate integration of the present network with other EC-funded networks and with the European and global post-genomic community. genomics data handling and standardisation.This will require a concerted effort towards codification of the various biological assays according to specific functional features analysed by each assay,using for example the Gene Ontology as a template (www.geneontology.org),and the sharing of analysis software and tools.Towards the same aim, a web-accessible platform based on the Distributed Annotation System (www.biodas.org) will be implemented. IV. Development of tools for diagnostic validation of molecular signatures for cancers of high population impact,namely:colon,breast and lung. This will enable translation into clinical use of signatures obtained through the cancer-oriented genomic screenings performed by the participating units.In particular,the project is expected to define and validate prognostic signatures associated with the tendency of the above mentioned cancers to give rise to metastasis.
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Research activities
To reach the proposed goals, TRANSFOG is structured in seven research activities, here briefly outlined. 1. Cancer-oriented genomic screenings in tumours and cell lines Genome-wide screenings by DNA microarrays, array-CGH, epigenetic and proteomics will be carried out on tumour samples selected for metastatic progression of breast, colon and lung carcinomas, as well as on cancer-oriented experimental models,like serine and tyrosine kinase receptor-driven transcriptional responses,ligand-induced in vitro epithelial morphogenesis and invasive growth, in vitro angiogenesis of endothelial cells.The results of the screenings will be integrated to generate a wide panel of previously uncharacterised genes that are potentially involved in basic biological functions underlying cancer progression, such as cell growth, apoptosis, motility, invasion, morphogenesis and others. 2. Development of enabling technologies for systematic gene gain-offunction Among the possible approaches to functional characterisation of candidate genes identified by Activity 1, one is based on enabling the expression of their full-length (FL)-cDNAs in cells of interest or in bacteria for recombinant protein production. This will require the assembly of a core FL-cDNA collection, which is a strategic delivery of TRANSFOG. 3. Generation of a siRNA vector collection to enable systematic gene lossof-function analysis A second way to analyse the function of genes is by inducing lossof-function. This can be achieved also in mammalian cells by RNA silencing technologies (Science 296:550-553, 2002). Some of the participating groups have already set up these technologies. This know-how will be exploited for a key effort of the present project, that is the generation of a shared collection of thousands of human siRNA constructs in a plasmid/retroviral expression system (which allows easy further transfer of the construct in the target cells of choice), mainly targeting genes of unknown function that gain high priority for TRANSFOG partners through their cancer-oriented genomic explorations described in Activity 1.The use of single-gene silencing RNA species will allow the identification of individual gene functions whereas combinatorial approaches will allow the characterisation of polypeptides active in the same cellular pathways. 4. Development of high-throughput functional assays Many of the participants have previously developed and employed simple assays on cultured cells to evaluate growth, motility, survival, invasion, adhesion, morphogenesis, transformation, angiogenesis and other basic biological functions altered during tumour progression and metastasis. Modulation of these functions by the candidate genes will be assessed by systematic transduction of cultured cells with FL-cDNAs or siRNAs subcloned in expression vectors. Some of the proposed
assays will reach an adequate throughput for studying all identified candidates, while other assays, exploring more complex processes, will most likely require additional candidate prioritisation. Largescale siRNA analysis will also be carried out on Drosophila cells to identify genes relevant to cell motility. Mouse transgenic and knockout approaches will provide information on the in vivo role of the identified candidates in cancer progression and provide the final validation of new molecular targets for cancer therapy. 5. Proteomic approaches to the study of signal transduction and proteinprotein interactions Protein-protein interactions play a key role in a wide range of biological processes related to cancer progression. TRANSFOG partners will set up procedures for high-throughput analysis of multiprotein complexes by mass spectrometry, protein microarrays, Biacore biosensor analysis and cell-based protein-protein interaction systems. Some of these procedures will take advantage of the FLcDNA collection, which will provide the basis for highly parallel protein synthesis and purification. 6. Preliminary diagnostic validation of molecular cancer signatures Converting a molecular signature emerged from a cancer genomic screening into a validated tool for clinical use is a demanding task. For instance, the platform originally used to define the signature (e.g. a certain type of microarray) may not be the most adequate for subsequent capillary diffusion of the signature assay.A translational research phase is therefore required in which the signature of interest is re-assessed on new tumour samples and with other platforms (e.g. realtime PCR, tissue microarrays, immunohistochemistry), and cross-comparisons are made between platforms available at different sites. Standardised procedure will be defined for the various platforms, and for the management of data of both clinical and experimental nature. The main diagnostic problem that the TRANSFOG project plans to address is the prediction of the probability with which a primary carcinoma of the colon, lung and breast will give rise to metastasis. 7. Generation of a common platform for data handling and gene functional annotation Efficient handling and sharing of genomic profiles and gene functional annotation will be achieved by development of an integrated, webaccessible data handling system with annotation tools for analysis of gene expression and function.The partner EMBL-EBI will provide the necessary expertise in collaboration with bioinformatic personnel of the other partners.
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Coordinator
Prof. Storme, Guy GEIE-LINC (Groupement Europen dIntrt Economique - Liaison Network for Cancer) c/o AZ-VUB Cancer Centre Laarbeeklaan 101 1090 Brussels, Belgium Phone: + 32 2 477 61 47 Fax: + 32 2 477 62 12 Project web-site: http://transfog.org Prof. Medico, Enzio The Oncogenomics Center Institute for Cancer Research and Treatment S.P. 142 km 3.95 10060 Candiolo (TO), Italy Phone: + 39 011 993 3234 Fax: + 39 011 993 3225 E-mail: enzo.medico@ircc.it Keywords: Oncology, Genomics, Proteomics.
Partners
CNIO, Spain DKFZ, Germany NKI,The Netherlands IRCC, Italy UMCU,The Netherlands IFOM, Italy EMBL-EBI, United Kingdom.
Acronym: TRANSFOG Project number: LSHC-CT-2004-503438 EC contribution: 6 000 000 Instrument: Integrated Project Duration: 48 months Starting date: 01/06/2004
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FIRST
CANCER
Further improvement of radiotherapy of cancer through side-effect reduction by application of adult stem cell therapy
Summary
Radiotherapy is the second most important treatment modality after surgery in the treatment of cancer.At present over 50% of all cancer patients receive radiotherapy at one stage in their course. Inevitably normal tissues are also exposed to ionising radiation during radiotherapy of tumours. This can result in organ failure and hence can seriously limit the treatment dose. Reduction of the side-effects of radiotherapy will not only increase the quality of life after the treatment but may also result in increased survival of cancer patients as it will allow dose escalation to the tumour. This is true even if the most optimal physical dose delivery (conformal therapy, protons) of radiation is applied. Radiation-induced organ failure is mainly caused by stem cell sterilisation, leading to a reduced reconstitution of functional cells.The innovative vision of this project is to reduce radiation-induced complications through stem cell therapy. Replenishment of the depleted stem cell compartment should allow regeneration of irradiated tissues. A successful replacement of stem cells and subsequent amelioration of radiation-induced complications may open the road to completely new strategies in radiotherapy and help combat cancer. marrow.However,tissue specific cells are only available in small numbers. Therefore, bone marrow stem cells have the largest clinical potential to be used for transplantation into irradiated organisms or individual normal tissues to provide the organ with sufficient numbers of cells necessary for regeneration. The FIRST project consists of two blocks of works (BOW). In BOW1 normal tissue radiobiologists are brought together to use established animal models to study the effects of cell therapy after radiotherapy.The cell therapy protocols are delivered by stem cell biologist working in BOW2.
Aim
The aim of the project is to develop and optimise techniques to prevent radiation-induced normal tissue complications using adult stem cell therapy. The tissues of interest will be oral mucosa, skin, gut and salivary gland tissues.The first step will be to provide proof of principle for the impact of stem cells on the repair of irradiated tissues. To this end protocols for the isolation, mobilisation, and characterisation of bone marrow derived stem cells will be performed and developed. Specific targeted approaches for transplantation of bone marrow derived stem cells will be designed and tested.
Problem
Many attempts have been made to attenuate radiation-induced damage to normal tissues.Although much knowledge has been obtained on the mechanism of radiosensitivity of normal tissue, and the pathogenic pathways that eventually result in loss of function, the vast majority of remedies are either inadequate,diminish in time or have not been shown to be selective for normal tissue only. Therefore a completely new approach is needed. Today bone marrow transplantation is common clinical practice. Due to new scientific knowledge and biotechnological developments,only recently it has become apparent that bone marrow transplantation may rescue other organs. Moreover, cells from certain tissues may even repopulate the haematopoietic system.Similar findings have been reported for stem cells derived from other tissues than bone
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Expected results:
1. optimised protocols for isolation, generation, mobilisation, characterisation and expansion of stem cells from bone marrow 2. demonstration of proof of principle for the use of bone marrowderived stem cells to modificate radiation-induced normal tissue damage in animal models.
Potential applications:
The resulting scientific and (bio)technological knowledge and a successful replacement of stem cells and subsequent amelioration of radiationinduced complications may eventually lead to new and improved cancer treatment strategies which will profoundly increase radiotherapy treatment success.
The blocks of work (BOW) are divided into workpackages (wp).Workpackage 1-4 are the normal tissues studied.They use together with other partners the methods described to determine the success of transplantation.WP 5-8 concerns the different stem cell types and protocols, common techniques are shared and are distributed to BOW1.TUD (P5): Medical Faculty Carl Gustav Carus, Radiobiology Laboratory, Prof. Dr.Wolfgang Drr (D). CEA (P3): CEA- Service de Gnomique Fonctionnelle, Dr. Michle Martin (F). University of Groningen, RSCB (P1) Radiation and Stress Cell Biology, Dr. Robert Coppes (Co-ordinator, NL), IRSN (P3) IRSN, Dpartement de Radioprotection de la Sante de l'Homme et de Dosimetrie, Dr. Dominique Thierry (F). SCB (P2), University of Groningen, Stem Cell Biology Prof. Dr. Gerald de Haan (NL), LH (P7) Universit Franois Rabelais, Facult de Mdecine, Laboratoire d'Hmatopose. Dr. Pierre Charbord (F). 7TM, 7TM Pharma A/S, Hrsholm, Prof. Dr.Thue Schwartz (DK).
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Coordinator
Dr Coppes, Rob Department of Radiation and Stress Cell Biology Faculty of Medical Sciences University of Groningen A. Deusinglaan 1 9713 AV Groningen,The Netherlands Phone: + 31 50 3632709 Fax: + 31 50 3632913 E-mail: r.p.coppes@med.rug.nl Project web-site: http://www.rug.nl/med/onderzoek/internationaleprojecten/europeseprojecten/first (in preparation) Key words: radiation-induced complications, adult stem cell therapy, cancer therapy
Acronym: FIRST Project number: LSHC-CT-2004-503436 EC contribution: 1 500 000 Instrument: Integrated Project Duration: 24 months Starting date: 01/09/2004
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CANCERDEGRADOME
Extracellular proteases and the cancer degradome: Innovative diagnostic markers, therapeutic targets and tumour imaging agents
Summary
Extracellular proteases have complex roles with distinct functions at different stages of tumour development and progression,and may have conflicting effects on malignancy. The complete repertoire of extracellular proteases through which cells regulate their local environment is termed the Degradome. Extracellular proteases remain an attractive target for intervention against cancer and we propose to transfer recent insights into their function to pre-clinical and clinical settings.
Problem
The critical defining feature of a malignant tumour is the presence of cells that have broken through tissue boundaries and penetrated into surrounding normal tissues. It has long been recognised that cellular invasion of basement membranes and connective tissue stroma involves the actions of diverse extracellular proteases from multiple enzymatic classes, including the metalloproteinases (MPs) and the serine,threonine,thiol and aspartic proteases,which can be produced either by cancer cells themselves or by neighbouring host cells.These cellular proteases participate also in the formation of new blood vessels that support the burgeoning energy demands of a rapidly growing tumour, and in the ability of cancer cells to metastasize to distant organs. They constitute the Degradome the complete repertoire of proteases that cells and tissues coordinatively regulate in order to modulate their local environment. We now understand that pericellular proteolysis is important in the regulation of: 1) growth factor activation, bioavailability and receptor signalling; 2) cell adhesion and motility, 3) apoptosis and survival mechanisms; 4) angiogenesis; 5) specification of cellular identity,and 6) inflammatory responses and immune surveillance. In the battle against cancer, the Degradome is important in three principal areas. 1) Cellular proteases and their inhibitors are components of the molecular machinery of malignancy, and thus are attractive as therapeutic targets. 2) Degradome genes are valuable as prognostic and diagnostic markers of disease that can improve the accuracy of conventional clinical and histopathological assessment.
3) Cellular proteases are target molecules for improving tumour detection and imaging. The goals in molecular diagnostics are to develop molecular profiling technologies and markers of disease status that are broadly applicable to the selection of patients for therapy, or to screening of diseasefree individuals who may benefit from prophylactic interventions.
Aim
The aim of this project is to define new molecular targets for drug design and to develop novel specific interventions that are based on thorough knowledge of the pathophysiological roles of target proteases and related molecules, and to understand how and when to use them. The identification of new molecular diagnostic and prognostic indicators of patient risk, together with new ways to enhance visualisation of tumours in the clinic,will improve health care delivery based on an individualised, patient-oriented approach to cancer therapy.
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Expected results
1.The determination of Degradome gene expression patterns in human tumour cell lines and mouse models. 2. A detailed analysis of Degradome gene function using tumour prone mouse models. 3.The analysis of protease inhibitor function in combination with other therapies. 4. Elucidation of the interplay between proteases and other key molecules of intracellular and intercellular signalling. 5. Determination of the regulatory factors that control protease gene expression in tumours and in the tumour-host dialogue. 6. Characterisation of the cellular expression of Degradome genes for breast and prostate cancer. 7. Development of metalloproteinases. active site-directed inhibitors of
Several major pharmaceutical companies have been involved in the development of synthetic protease inhibitors for cancer therapy over the past decade. However, the vast majority of trials have shown these first generation compounds to have limited effects.What is now clear is that the biological activities of extracellular proteases,and their roles in normal and diseased tissues, are much more complex than was originally envisioned.The original notion of proteases solely as mediators of pathological tissue destruction is an oversimplification: in fact, some proteases have functions that inhibit tumour development and progression, and moreover, their natural inhibitors (TIMPs, PAIs, etc) can in some instances enhance tumourigenesis. The identification of protease targets for the design of novel and specific interventions will offer improvements for health care delivery and patient management. The knowledge obtained in this project can also be used to identify cancer susceptibility in otherwise healthy individuals.
8. Development of ligands able to prevent the formation of proteasesubstrate, protease-inhibitor, protease-receptor complexes. 9. Production of radiotracers for protease ligands for in vivo imaging, with transfer to clinical paradigms.
Overview of rat, mouse, and human degradomes.This figure represents the complete set of protease and protease homologue genes from the indicated species.
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Coordinator
Prof. Edwards, Dylan School of Biological Sciences University of East Anglia Norwich NR4 7TJ, United Kingsom Phone:+ 44 1603 592184 Fax: + 44 1603 593222 E-mail: dylan.edwards@uea.ac.uk Project web-site: http://www.cancerdegradome.org/ Key words: cancer, metalloproteinase, protease, metastasis, diagnostics, tumour imaging
Faculty of Chemistry, National and Kapodistrian University of Athens, Greece Ecole Polytechnique Federale de Lausanne, Switzerland Institut fr Molekulare Medizin und Zellforschung, Freiburg, Germany Dept of Genetic Toxicology, National Institute of Biology, Ljubljana, Slovenia Mario Negri Institute for Pharmacological Research, Bergamo, Italy Humboldt University, Berlin, Germany Division of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch, France Institut fur Experimentelle Onkologie und Therapieforschung,Technical University of Munich, Germany Proteros Biostructures GmbH, Martinsried, Germany Division of Carcinogenesis and Differentiation, Deutsches Krebsforschungszentrum, Heidelberg, Germany Dept of Molecular Biology, University of Aarhus, Denmark Institute of Genetics and Biophysics Adriano BuzzatiTraverso, Naples, Italy Istituto di Endocrinologia e Oncologia Sperimentale G. Salvatore, Naples, Italy Institut de Biologia Molecular de Barcelona, Spain University of Southampton Human Genetics Division, School of Medicine, United Kingdom OncoMethylome Sciences SA, Lige, Belgium Genoptics SA, Orsay, France Laboratory for Radiopharmacy, University of Ghent, Belgium KRKA, Department of Biochemical Research and Drug Design, Lujbljana, Slovenia Institute of Pathology, Cantonal Hospital, University of Basel, Switzerland
Partners
The Finsen Laboratory, Copenhagen University Hospital, Denmark IFOM Institute of Molecular Oncology, Milan, Italy CRCE Faculty of Medicine, University of Lige, Belgium Dpto de Bioquimica y Biologia Molecular, Universidad de Oviedo, Spain Cambridge Institute of Medical Research, University of Cambridge, United Kingdom Dept Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden Departement d-Ingenierie et deEtudes des Proteines, Gif-sur-Yvette, France Unit d'Imagerie de l'Expression des Genes, Orsay, France Laboratory for Experimental Oncology, Department of Medical Oncology, University Hospital Gasthuisberg, Leuven, Belgium Centre for Biotechnology,Turku, Finland VTT Medical Biotechnology Group,Turku, Finland Dept. of Vascular Biology & Thrombosis Research, University of Vienna, Austria Max Planck Institute for Biochemistry, PlaneggMartinsried, Germany
Acronym: CANCERDEGRADOME Project number: LSHC-CT-2003-503297 EC contribution: 10 400 000 Instrument: Integrated Project Duration: 48 months Starting date: 01/01/2004
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Selective targeting of angiogenesis and of tumor stroma

Summary
Targeted delivery of therapeutic agents to the tumor microenvironment is a novel avenue for cancer treatment toward the development of more efficacious and better-tolerated anticancer drugs. This project aims to identify new molecular targets which are selectively expressed in tumor stroma and in the neo-vasculature of aggressive tumors and to develop new therapeutic strategies based on high affinity binding molecules capable of selective localization in tumor stroma and/or vascular structures. Efforts to move the most promising product(s) generated within this Integrated Project into Clinical Trials is the ultimate scope of the project. Potential application is the pharmacological treatment of solid neoplasms, maintaining or improving present percentage of respondents, survival, disease-free interval, with improved safety and a better quality of life. European Network in research and in the pharmaceutical development of ligand-based,targeted anti-cancer therapies,with a particular emphasis on the targeting of tumor neo-vasculature and tumor stroma. This project focuses on the: - Identification and validation of molecular targets which are selectively expressed in the stroma and in neo-vascular sites of aggressive solid tumors. Endothelial cells and stromal cells are genetically more stable than tumor cells and can produce abundant markers, which are ideally suited for tumor targeting strategies. - Isolation of high-affinity binding molecules [small organic compounds, antibodies], which are specific for markers of angiogenesis and/or the tumor stroma, and are capable of selective localization in the tumor environment, after intravenous administration. - Development of therapeutic strategies, based on specific binding molecules capable of selective localization around tumor vascular structures and/or in the tumor stroma. - Dissemination of the research activities of the Project.
Expected results
Problem
The majority of pharmacological approaches for the treatment of solid tumors suffers from poor selectivity, thus limiting dose escalation (i.e., the doses of drug which are required to kill tumor cells cause unacceptable toxicities to normal tissues).The situation is made more dramatic by the fact that the majority of anticancer drugs accumulate preferentially in normal tissues rather than in neoplastic sites,due to the irregular vasculature and to the high interstitial pressure of solid tumors. One avenue towards the development of more efficacious and better tolerated anti-cancer drugs relies on the targeted delivery of therapeutic agents to the tumor environment, thus sparing normal tissues. This experimental strategy requires a range of diverse experimental techniques, for the identification of targets, for the isolation of binding molecules, and for their conversion into imaging and therapeutic products. Our approach has the potential advantage that immunohistochemistry, imaging and biodistribution data provide information about the selectivity of the anti-cancer drugs at several stages of the drug development process,and allow a rational optimization of the most promising lead compounds.
Flow-chart, outlining the main expected results, leading from target identification to the development of novel anticancer therapeutics.
Aim
In the past,our Consortium has developed innovative anti-cancer imaging and therapeutic strategies, based on recombinant antibody fragments, which have moved from the bench to the clinic. With the STROMA Project, we plan to strengthen and extend a leading position of our
We will consider the project as fully successful if at least one molecule enters clinical development for pharmacological treatment of solid neoplasms, maintaning or improving present percentage of respondents, survival, disease-free interval, with improved safety and better quality of life.
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Coordinator
Dr Giavazzi, Raffaella Laboratory of the Biology and Treatment of Metastasis Department of Oncology Istituto di Ricerche Farmacologiche Mario Negri Via Gavazzeni 11 24125 Bergamo, Italy Phone: + 39 035 319888 Fax: + 39 035 319331 E-mail: giavazzi@marionegri.it Project web-site: http://www.esh.org/DEFAULT/STROMA/sconsortium.htm Key words: neoplasm, stroma, angiogenesis, selective targeting, combination therapy, antibody, small molecules, oncofetal antigens, tumour neo-vasculature
Partners
Prof. Bikfalvi, Andreas Molecular Mechanisms of Angiogenesis Laboratory INSERM E 0113 Institut National de la Sant et de la Recherche Medicale Universit Bordeaux 1 Talence, France Dr Bicknell, Roy Molecular Angiogenesis Laboratory Cancer Research UK, Institute of Molecular Medicine University of Oxford John Radcliffe Hospital Oxford, United Kingdom Prof. Neri, Dario Institute of Pharmaceutical Sciences Swiss Federal Institute of Technology ETH Hnggerberg Zurich, Switzerland Prof. Begent, Richard Royal Free Campus Department of Oncology University College London London, United Kingdom Prof. Zardi, Luciano Istituto Giannina Gaslini Centro di Biotecnologie Avanzate, Istituto Nazionale per la Ricerca sul Cancro Genova, Italy
Prof. Castronovo,Vincent Facult de Mdecine Laboratoire de Recherche sur les Metastases Universit de Lige Lige, Belgium Prof. van Dongen, Guus Laboratory for Tumour Biology Department of Otolaryngology VU University Medical Center, Amsterdam,The Netherlands Dr Zanda, Matteo Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche Milan, Italy Dr Vajkoczy, Peter Faculty for Clinical Medicine Mannheim Department of Neurosurgery Ruprecht-Karls-Universitt Heidelberg Mannheim, Germany Prof. Kosmehl, Hartwig Institute of Pathology Helios Klinikum Erfurt GmbH Erfurt, Germany Dr Dinkelborg, Ludger Radiopharmaceuticals Research Schering AG Berlin, Germany Dr Viti, Francesca Philogen s.r.l. Siena, Italy Dr Umaa, Pablo Glycart biotechnology AG,Wagistrasse 18 Zurich, Switzerland Dr Marsoni, Silvia Sendo Foundation Milan, Italy Dr Jasmin, Didi European School of Haematology Centre Hayem, Hpital Saint Louis Paris, France
Acronym: STROMA Project number: LSHC-CT-2003-503233 EC contribution: 6 000 000 Instrument: Integrated Project Duration: 48 months Starting date: 01/01/2004
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Mutant P53 as a target for improved cancer treatment

Summary
Mutations in the p53 tumour suppressor gene are the most frequent genetic alteration in human cancer, occurring in over 40% of all cases of cancer. One well-studied outcome of these mutations is the loss of the tumour suppressor activity of the wild type (wt) p53.However,there is growing evidence that many of the mutations that occur in the p53 protein generate mutant p53 proteins (mutp53) have acquired new biochemical and biological properties. Through this gain of function (GOF),mutp53 is believed to contribute actively to the cancer process. We propose to explore mutp53 as a target for novel anti-cancer therapies. Such therapies should aim to either abrogate the GOF effects of mutp53, or restore wt-like properties to mutp53, so that it can now regain its tumour suppressor capabilities. A multi-disciplinary approach will be undertaken to explore and exploit the contribution of mutp53 to cancer. One component of this project will investigate in depth the molecular properties of mutp53: structural studies will pinpoint the changes that particular mutations inflict on the structure of p53, and allow the classification of mutp53 into distinct subclasses. In parallel, biochemical studies will explore the mode of action of mutp53 within cells,including its impact on patterns of gene expression,identification of specific DNA sequences targeted by mutp53, and discovery of mutp53-interacting cellular proteins. Preclinical models for mutp53-driven cancer will also be developed, as a critical instrument for pre-clinical studies. The other component will aim at translating this wealth of information into better cancer therapy.One avenue will address the clinical relevance of particular p53 mutations in human cancer, particularly its impact on the patients response to chemotherapy.This should lead to guidelines for more effective use of conventional therapy.The other avenue will explore novel therapies targeted at mutp53 and mutp53-expressing tumour cells. A major effort will focus on the discovery of small compounds that can restore wtp53-like activity to mutp53.An innovative approach to immunotherapy directed against mutp53-overexpressing cancer cells will also be explored.Owing to the extremely high frequency of p53 mutations, the success of this project will impact on a very large number of cancer patients in Europe and worldwide. The p53 tumor suppressor pathway. p53 is normally an unstable protein but becomes stabilized in response to various forms of cellular stress, e.g. DNA damage, oncogenic singalling and hypoxia. The accumulation of p53 protein triggers cell cycle arrest, apoptosis and/or senescence.
Problem
Cancer is a major cause for human suffering in Europe as well as elsewhere in the world. It causes immense effects on the cancer patients themselves, on their families, as well as on society at large. In additional to the severe human suffering and their immediate societal impact, cancer treatment and management is also a major economic burden.The importance of this problem and the urgency of the need for novel approaches to cancer management and treatment have been recognised by the EC, as reflected by the establishment of a specific call in the area of Combating Cancer. Mutations in the p53 tumour suppressor gene are the most frequent genetic alteration in human cancer, occurring in over 40% of all cases of cancer.We propose to explore mutp53 as a target for novel anticancer therapies. Such therapies should aim to either abrogate the gain of function (GOF) effects of mutp53,or restore wt-like properties to mutp53,so that it can now regain its tumour suppressor capabilities. A multi-disciplinary approach will be undertaken to explore and exploit the contribution of mutp53 to cancer.
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Aim
In our proposed project, we introduce a multidisciplinary approach to explore mutp53 as a new target for innovative treatment. A primary objective of the Combating Cancer initiative is to combat cancer by developing improved patient-oriented strategies to better treatment with minimal side-effects with a focus on encouraging the development of evidence-based guidelines for good clinical practice. Our project meets these requirements in at least two distinct ways: 1.We aim to improve the use of contemporary chemotherapy through providing better guidelines based on correlations between p53 genotype of the tumour and its response to particular types of anti-cancer drugs. It is important to keep in mind that, although novel therapeutic approaches are very exciting and promising, millions of cancer patients all over Europe are being treated every day with standard chemotherapy.Beyond its limited efficacy,this is also associated with significant toxicity and therefore often unjustified patient suffering. The ability to make better predictions as to which particular chemotherapeutic regimen is most likely to work for a particular patient thus has far-reaching implications, both in ensuring better and more effective treatment and,not less importantly,in preventing unnecessary suffering from severe side-effects in cases where it is clear that a particular treatment is not going to work.Providing new recommendations to oncologists, allowing them to individualise the chemotherapy course chosen for a given patient, will therefore meet the objective of better treatment with minimal side-effects, and will provide evidence-based guidelines for good clinical practice. 2.A major component of this project is aimed at developing novel therapies, based on mutp53 knowledge to be gained by the consortium. The increased selectivity and specificity of such drugs is most likely to reduce side-effects on normal patient tissue, because such tissue does not express any mutp53,unlike the targeted tumour cells.Thus, any successful drug that comes out of this project is highly likely to lead to improved clinical practice and to better treatment, with reduced side-effects as compared to the presently available options. Moreover, the fact that close to half of all human tumours possess mutp53 in abundant amounts makes any new drug emanating from this endeavour potentially valuable to a very large number of cancer patients.Such drug,if successful,may thus have far-reaching impacts, not only on individual cancer patients, but also on European society as a whole.
p53 is a transcription factor that binds specific DNA motifs in p53 target genes and activates transcription.The consensus p53 binding motif is RRRCWWGYYY N013 RRRCWWGYYY where R is purine,W is A or T, and Y is pyrimidine.
p53 missense mutations in human tumors cluster in the DNAbinding core domain (approximately residues 100-300). So called hot spots mutations include Arg248 and Arg273 (DNA contact mutants) and Arg175, Gly245, Arg249, and Arg282 (structural mutants).
3. explore in depth the structural properties of selected mutp53 proteins, in order to provide leads for structure-based rational drug design; 4. evaluate the impact of mutp53 status on the response of selected types of human tumours to chemotherapy,and use this information to formulate guidelines for more effective use of currently available anti-cancer therapies; 5. search for molecules and compounds that can selectively interfere with mutp53 GOF or restore wtp53 activity to mutp53,and explore them as potential anti-cancer drugs;. 6. initiate clinical trials (Phase I) with one mutp53-selective drug that has already gone successfully through pre-clinical studies; 7. generate leads and new tools towards the development of mutp53based immunotherapy.
Expected results
The proposed project will address the following main objectives: 1. elucidate the biochemical basis for mutp53 GOF (GOF),with special emphasis on genomics and proteomics approaches; 2. evaluate the contribution of mutp53 to the malignant properties of cancer cells;
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Cancer represents one of the most severe health problems in the European community. Cases are growing with the age of the population. The economic and emotional burden is enormous. Mutp53 protein is expressed in about 50% of all human tumours. In some categories with growing incidence, e.g. lung cancer, colon carcinoma and skin tumours, more than 60-70% of the tumours are associated with mutated p53.This may be due to the induction of p53 mutations by dietary and environmental carcinogenic insults, which are encouraged by modern western societys lifestyle (exposure to sun,very heavy smoking in most parts of Europe,high-fat diet). In some types of cancer, expression of mutp53 appears to be particularly highly correlated with the more aggressive tumour stages.Yet, in many cancers, mutation of p53 appears to occur during the very early steps of carcinogenesis.This is particularly true for cancers of the lung, head-and-neck, bladder, skin and oesophagus. In these pathologies, mutp53 is amongst the earliest tumourigenic changes that can be detected in the patient, sometimes ahead of the clinical diagnosis of a cancer lesion.The expression of mutp53 is relatively easy to diagnose, employing immunohistochemical assays that are already available as commercial kits and are in use in many pathology laboratories throughout Europe. However, there
Mutant p53 gain-offunction.Wild type (wt) p53 binds specific DNA motifs and activates p53 target genes. Mutant p53 fails to bind specific DNA motifs and activate p53 target genes. Putative gain-offunction activity of mutant p53 may include protein-protein interactions and illegitimate activation of targets that contribute to tumor progression.
Mutant p53 reactivation as a novel strategy for cancer therapy. Restoration of wild type conformation and function to abundant mutant p53 by a novel drug triggers massive apoptosis and thus eliminates the tumor.
An effective novel treatment of cancers expressing mutp53 could help to prolong life expectancy and quality of life. Such a treatment may be applicable for eradicating small lesions in pathologies where mutation is an early event, thus providing low-cost, low-stress approaches for lesions that are currently managed through surgery and/or chemotherapy. On the other hand, mutp53-based therapies can be applied synergistically with conventional therapy regimens in patients with advanced cancers.The mutp53-based approach thus opens a whole range of possibilities that can be implemented in current medical practice without costly equipment, infrastructures or extensive training programmes. Development of effective anti-cancer therapy for mutp53expressing tumours would lower direct and indirect costs by reduction of surgery and intensive care, reduction of duration of medical survey, reduction of emotional burden for patients and their family and faster reintegration of patients as part of the working economy. In addition, one should keep in mind that although novel anti-cancer therapies are a very exciting avenue, millions of cancer patients in Europe are presently being treated with conventional chemotherapy. Current chemotherapy has severe adverse effects on the quality of life of the treated patient.The combination of data from experimental model systems and the cancer patient mutp53 database might potentially identify groups of patients who are not suitable for particular types of contemporary chemotherapy. Better tools to decide which patients should be treated and which to be left untreated are extremely important in reducing the suffering of those patients who will not benefit from the currently available cancer therapy modalities.
is still a lack of rapid, low-cost and sensitive assays for mutation detection, and this is the key to the systematic implementation of mutp53-based strategies for cancer diagnosis, prognosis, and treatment.This is why one of the activities of our consortium will be to support the validation and the transfer into production of a new type of micro-array developed by Asperbio, an SME partner of our consortium. Improved detection of p53 mutations may enable earlier cancer diagnosis, increased curability and reduction in the societal impact of cancer morbidity and mortality.
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Coordinator
Prof.Wiman, Klas Karolinska Institute Department of Oncology-Pathology Cancer Center Karolinska (CCK), R8:04 Karolinska Hospital SE-171 76, Stockholm, Sweden Phone: + 46 8 5177 9342 Fax: + 46 8 32 10 47 E-mail: Klas.Wiman@cck.ki.se Project web-site: www.mutp53.com Key words: p53 tumour suppressor, mutations, gain-offunction, p53 status, clinical outcome, mutant p53-reactivating drugs, novel cancer therapy
Department of Chemistry, University of Cambridge, United Kingdom International Agency for Research on Cancer (WHO), Lyon, France Department of Hematology & Oncology, JohannesGutenberg-University Medical School, Mainz, Germany Department of Oncology-Pathology, Karolinska Hospital, Stockholm, Sweden Department of Molecular Cell Biology,The Weizmann Institute of Science, Rehovot, Israel Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic Laboratorio Oncogenesi Molecolare, Istituto Regina Elena - CRS, Rome, Italy Microbiology & Tumor Biology Center (MTC), Karolinska Institute, Stockholm, Sweden Dept. of Structural Biology,The Weizmann Institute of Science, Rehovot, Israel Division of Molecular Biology H8,The Netherlands Cancer Institute, Amsterdam,The Netherlands Johannes Gutenberg-University, Department of Hematology and Oncology, Mainz, Germany Asper Biotech,Tartu, Estonia GanyMed, Mainz, Germany Aprea AB, Karolinska Institute, Stockholm, Sweden
Partners
Division of Tumor Biology,The Netherlands Cancer Institute, Amsterdam,The Netherlands Department of Cell Cycle & Cancer, Institute of Cancer Biology, Copenhagen, Denmark Molecular Oncogenesis Laboratory, Regina Elena Cancer Center, Rome, Italy Department of Genetics, Institute for Cancer Research, Oslo, Norway Laboratorio Nazionale CIB,Trieste, Italy Heinrich-Pette Institute, Hamburg, Germany Department of Physics of Complex Systems,The Weizmann Institute of Science, Rehovot, Israel
Acronym: Mutp53 Project number: LSHC-CT-2004-502983 EC contribution: 8 000 000 Instrument: Integrated Project Duration: 60 months Starting date: 01/02/2004
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MOL CANCER MED
CANCER
Developing molecular medicines for cancer in the post-genome era

Summary
The cellular immortality enzyme telomerase (one of the most promising universal cancer markers) and associated telomere maintenance mechanisms represent novel anti-cancer targets of enormous therapeutic and diagnostic potential. In MOL CANCER MED, a multinational EU translational cancer research consortium has been established, in which expert cancer geneticists and molecular biologists will interact with prominent pharmacologists, clinicians and pathologists to develop these exciting new cellular targets into measurable pre-clinical advances, within a four-year time-frame. The project has been structured into three, highly interactive areas of activity, involving the fundamental evaluation and pre-clinical validation of: (i) telomerase as a target for cancer treatment and diagnosis based on new molecular knowledge about its expression and function, (ii) associated downstream telomere maintenance mechanisms as additional targets for novel drug design, and (iii) new anti-cancer drugs based on these targets.The consortium will bring to bear diverse and complementary technological know-how of considerable power to deliver the above primary objectives. Effective management will maximise synergies across MOL CANCER MED in order to produce genuine improvements in the design of new treatments that promise to be active against a broad spectrum of common human malignancies. to have evolved as a powerful protective barrier against cancer. Immortalisation in vitro of normal human cells that lack telomerase involves the reactivation of telomerase or, rarely, an alternative (ALT) mechanism for maintaining telomeres. It is clear that telomerase is obligatory for continuous tumour cell proliferation, clonal evolution and malignant progression. Because telomerase is found in around 90% of human cancers and is essential for the continued proliferation (and clonal evolution) of cancer cells, it represents one of the most exciting anti-cancer targets thus far discovered. Results with a variety of telomerase inhibitory strategies in human cancer cells have confirmed that its functional inactivation results in progressive telomere shortening, leading to growth arrest and/or cell death through apoptosis. Promising candidate small molecule inhibitors are beginning to emerge that will form the basis for anti-telomerase drug development. MOL CANCER MED is based on successful Framework 5 research concerned with establishing the value of the cellular immortality enzyme telomerase as an anti-cancer target (Project: QLG-199901341;TACIT) and represents an expansion and elaboration of this. TACIT yielded results that have triggered new translational research with clearly defined clinical applications.To this set of activities have been added carefully selected new EU research teams, notably in the area of drug development.
Aim
The principal aim of MOL CANCER MED is to fully exploit the results of recent fundamental advances in understanding the role of telomerase and telomere maintenance mechanisms in human cancer development, in order to achieve genuine clinical benefit (i.e. in developing both improved diagnostics and anti-cancer therapies). The principal measurable objectives of the project, over the complete 48 month period, are: (i) to validate further the potential of telomerase and telomere maintenance systems in cancer therapy and diagnosis, (ii) to identify novel molecular targets based on
Problem
Cancer is a leading cause of death in the western world, second only to cardiovascular disease, and is therefore a European public health problem of overwhelming human and economic significance. The incidence of cancer is set to increase substantially with demographic and possibly environmental influences playing a part. However, there is now an improved molecular understanding of the key genetic, biochemical and cellular changes leading to cancer, in significant part due to the efforts of diverse groups of world-class EU-based scientists. With the completion of the human genome sequence imminent, it is now timely to initiate a major European coordinated effort to translate fundamental scientific knowledge about cancer into safer, more effective, therapies and improved early diagnostic procedures. MOL CANCER MED is focused on a single group of highly promising anti-cancer targets associated with telomerase and telomere maintenance. Repression of telomerase in the somatic tissues of humans, and probably other long-lived mammals, appears
(A) Normal human skin (B) organotypic culture of the immortal HaCat skin keratinocytes Both are co-stained with an antibody against hTERT (red nuclear staining) and an antibody decorating the basement membrane (green staining). All nuclei are counterstained with DAPI (in blue)
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telomere structure, function & stability, that may be of value in treatment and diagnosis of the common human cancers, (iii) to create a programme of novel small molecule drug development based initially on recently identified (but thus far poorly exploited) targets and, later (from month 12 onwards) exploiting completely new targets identified during the project.
The emphasis of the LIFESCIHEALTH Priority is very firmly placed upon multidisciplinary translational research, in which fundamental scientific knowledge is harnessed for the specific purpose of generating, within the timeframe of FP6, reagents, treatments and diagnostics that are of clinical value. In MOL CANCER MED, a highly focused strategy will be adopted towards applying molecular genetic knowledge about the mechanisms underlying the cancer process to the development of completely new approaches to cancer treatment, eg in bringing molecular biology, cell biology, genomics and target evaluation together with small molecule drug discovery.
Expected results
1. Novel anti-cancer drug targets and diagnostic methodologies derived from advances in: (i) the understanding and definition of biochemical response pathways underpinning the telomere checkpoint for somatic cell proliferation, (ii) the identification and molecular/functional characterisation of natural mechanisms of telomerase repression and cell self-renewal (including hTERT repressor genes and chromatin remodelling factors) in normal human cells and their dysregulation in human cancers, and (iii) understanding the mechanisms of action and pharmacological activity of existing small molecule telomerase inhibitors (eg BIBR1532), and (iv) establishment of the precise roles of telomere aggregates and telomere-length-independent functions of telomerase in human cancer. 2. An advanced molecular understanding of telomerase regulation at chromosome ends (eg involving the key telomere-binding proteins POT1 and hEST1A) and a comprehensive evaluation of such proteins as anti-telomerase drug targets 3. New and effective molecular inhibitors (eg siRNAs, ribozymes & peptide nucleic acids) of telomerase and telomere maintenance (targeting hTERT transcription and telomere-related proteins discovered within the MOL CANCER MED Consortium) for the purpose of vasli. 4. Panels of new molecular markers of telomerase repression, telomere maintenance and associated signalling pathways, that can be developed into precise, rapid assays for use in novel kits for early cancer diagnosis and prognostic evaluation. 5. An understanding of the differential effects of telomerase/telomere maintenance inhibition on normal human tissues and in cancers using organotypic in vitro human cell models. 6. Rational design of libraries of novel small molecule compounds for screening against new targets, and selection of small molecule antitelomerase/telomere maintenance drug leads active against individual new targets discovered during the course of MOL CANCER MED. 7. Identification of potential anti-cancer drugs from the above, following biochemical, pharmacological and functional (in vitro and in vivo) anti-tumour assays. 8. Preclinical exploitation of potential novel cancer drugs through interface with clinical oncology centres and SMEs.
Human Telomeres
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Coordinator
Prof. Newbold, Robert Brunel University Kingston Lane Uxbridge UB8 3PH, United Kingdom Phone: + 44 1895 203090 E-mail: robert.newbold@brunel.ac.uk Project web-site: www.brunel.ac.uk/research/molcancermed/ Key words: cancer, therapy, genome, telomerase, diagnosis, drugs
Dr Parkinson, Kenneth University of Glasgow Glasgow, United Kingdom Dr Martens, Uwe Medical University Center Freiburg Freiburg, Germany Prof. Boukamp, Petra DKFZ Heidelberg, Germany Dr Blasco, Maria CNIO Madrid, Spain Prof. Keith, Nicol University of Glasgow Glasgow, United Kingdom Dr Zaffaroni, Nadia National Cancer Institute Milan, Italy Dr Serakinci, Nedime University of Aarhus Aarhus, Denmark Dr Roos, Goran Umea University Umea, Sweden
Partners
Prof. Neidle, Stephen London School of Pharmacy London, United Kingdom Dr Mergny, Jean-Louis INSERM Paris, France Prof. Mann, John Queens University Belfast Belfast, United Kingdom Dr DIncalci, Maurizio Istituto de Richerche Mario Negri Milan, Italy Dr Lingner, Joachim ISREC Epalinges, Switzerland
Acronym: MOL CANCER MED Project number: LSHC-CT-2004-502943 EC contribution: 4 000 000 Instrument: Integrated Project Duration: 48 months Starting date: 01/10/04
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EUROXY
Targeting newly discovered oxygen-sensing cascades for novel cancer treatments

Summary
The last decade's basic and clinical oncology research has revealed a number of so far unrecognised regulating responses (e.g.HIF-1) in cells exposed to hypoxia. These processes have been proven to have a major impact on tumour progression and resistance to radiotherapy and certain types of chemotherapy. Because of their strong over-expression in solid cancer tumours in comparison to adjacent normal tissue of these processes, this new knowledge may open a therapeutic window for cancer treatment by utilising hypoxia-responsive processes as drug targets. Over the first two to three years we will dissect relevant steps in cancer cell response to hypoxia, develop a technology platform for in vitro control of oxygen tensions peri-cellularly, further identify and characterise marker/target molecules, and do the initial in vitro drug development. Our mid-term evaluation will then select which hypoxic processes may be suitable as targets for cancer-specific treatment. Simultaneously, we will study diagnostic tagging and therapeutic strategies leading up to a selection process of promising compounds to be further developed after the end of the project period. The new treatments will be developed along two lines:targeting known cytostatics towards the newly discovered hypoxia-responsive molecules and searching for so far unused compounds, preferably toxic to pathways active during hypoxia. The consortiums final effort shall ensure industry use of our results.
Coordinator
Ebbesen, Peter Laboratory of Stem Cell Research Research Park Gustav Wiedsvej 10 8000 Aarhus C, Denmark Phone: + 45 86 12 73 66 Fax: + 45 86 19 54 15 E-mail: ebbesen@lsr.auc.dk Key words: Biology Equipment, Drug Candidates, Hypoxia, HIF-1, CA IX, Preclinical, Drug Development.
Partners
AstraZeneca UK Limited, United Kingdom Aventis Pharma, France Institute of Biotechnology - Lithuania Charit - Universittsmedizin Berlin, Campus Virchow Klinikum, Germany University of Zurich, Switzerland Deutsches Herzzentrum Mnche, Klinik an der TU Mnchen, Germany Jobst Technologies GmbH, Germany Universiteit Maastricht / Research Institute GROW, Maastricht,The Netherlands LEA Medizintechnik GmbH, Germany Leo Pharma A/S, Denmark Imperial College of Science,Technolgy and Medicine, United Kingdom Oxford BioMedica Plc, Oxford, United Kingdom Institute of Virology, Slovak Academy of Sciences, Slovakia The University of Oslo, Norway Karolinska Institutet, Sweden The Chancellor, Masters and Scholars of the University of Oxford, Oxford, United Kingdom RiNA-Netzwerk RNA Technologien GmbH, Germany University of Florence, Department of Chemistry, Florence, Italy The Victoria University of Manchester, Manchester, United Kingdom Albert Ludwigs University Freiburg, Freiburg, Germany ViVoX ApS, Denmark
Acronym: EUROXY Project number: LSHC-CT-2003-502932 EC contribution: 8 000 000 Instrument: Integrated Project Duration: 60 months Starting date: 01/02/2004
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MAESTRO
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Summary
At the beginning of the third millennium one European citizen out of three will have to deal with a cancer episode in the course of his/her life.Worldwide the estimated number of new cancer cases each year is expected to rise from 10 million in 2000 to 15 million by 2020.Cancer is currently the cause of 12% of all deaths worldwide. Within the European Union over 2 million new cancer cases are diagnosed every year and over 1 million people die of cancer.The two leading cause of cancers in Europe are breast and prostate.Therefore combating cancer is a major societal and economic issue for Europe. To face these new challenges strong mobilisation among the scientific community and industrial manufacturers is needed. Todays approaches to treat cancer are the surgical removal of the tumour tissue, radiotherapy, chemotherapy, and emerging immunotherapy.Among them radiotherapy remains a major technique to treat cancer. More than a half of all cancer patients are treated by radiation therapy thanks to the technical progress made with irradiation equipment in the last years. For external radiation therapy (RT), highenergy photon or electron beams are mainly produced by linear accelerators, for internal radiation therapy or brachytherapy, radioactive sources are put in the tumour with undeniable advantages for the patient in given situations.
- adaptive radiation delivery, tracking and control for radiotherapy (WP1), - radiotherapy software development (WP2), - sensors for dose evaluation in radiotherapy (WP3), - clinical requirements, protocols and validation (WP4), - organs at risk assessment studies (WP4), - clinical workshops for training and dissemination purposes (WP5), - management (WP6)
Expected results
The project has the potential to accelerate development of advanced devices, to ensure their dissemination, to increase the compromise between treatment efficiency and patient safety, to consolidate collaboration between European teams and to spread new methods and knowledge through workshops. A major expected result of the project is to decrease the number of deaths due to primary tumours without metastases.
Coordinator
Jean-Philippe Nicola Commissariat lEnergie Atomique (CEA) 31-33, rue de la Fdration 75752 Paris France E-mail: jean-philippe.nicolai@cea.fr Project web-site: www.maestro-research.org Key words: quality assurance, clinical validation, IMRT, protontherapy, multimodality image registration, virtual simulation software, Monte Carlo dose calculation TPS, in vivo dosimeters, risk assessment, accurate patient positioning
Aim
The present project,MAESTRO,proposes innovative research to develop and validate in clinical conditions the advanced methods and equipment needed in cancer treatment for new modalities in high conformal external radiotherapy employing electrons,photons and protons beams. The project aims at improving the conformation of the dose delivered to the target (tumoural tissues) whatever its shape in order to spare the surrounding tissues.To do this new technologies in the field of patient positionning and organ tracking,advanced software for treatment planning system,dose calculation and measurement,are to be developed,and linked to the emerging IMRT (Intensity-Modulated RadiationTherapy) technique.
Partners
Ion Beam Applications S.A, Belgium Technische Universiteit Delft,The Netherlands Istituto Nazionale Di Fisica Nucleare, Italy Dosisoft S.A, France Instytut Fizyki Jadrowej Im. Henrika Niewodniczanskiego, Polska Akademia Nauk, Poland Eldim S.A, France Nuclear Research and Consultancy Group,The Netherlands Universita Degli Studi Di Firenze, Italy REM Radioterapia SRL, Italy Istituto Superiore Di Sanita, Italy Coventry University, United-Kingdom NPL Management Limited, United-Kingdom Institut Gustave Roussy, France Centre National de la Recharche Scientifique, France Centre National Franois Baclesse, France Universitaet Duisburg-Essen, Germany University of East Anglia, United Kingdom Universidad de Castilla, La Mancha - Spain University Hospitals Coventry and Warwickshire NHS Trust, United Kingdom Centrum Onkologii Oddzial W Krakowie, Poland Institut National de la Recherche en Informatique et en Automatique, France Universitat de Barcelona, Spain Scanditronix Medical AB, Sweden
Programme of activities
MAESTRO incorporates major research and technological development programmes involving clinics and manufacturers which will be linked throughout. The project includes four work packages on research and development activities and two work packages of training and management activities:
Acronym: MAESTRO Project number: LSHC-CT-2004-503564 EC contribution: 7 000 000 Instrument: Integrated Project Duration: 60 months Starting date: 01/05/2004
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CCPRB
Cancer control using population-based registries and biobanks

Summary
CCPRB is a Network of Excellence project within the Sixth Framework Programme of the European Union. It is aimed at improved control of cancer by facilitating research linking biobanks and cancer registries. The project involves a systematic quality assurance of European biobanks, as well as improved integrity protection in the handling of sensitive information in connection with biobank-based research.The samples in the biobanks will be used in large-scale cancer research searching for genetic and infectious causes to cancer, in particular in the areas of breast and colorectal cancer and childhood leukaemias.
Aim
Provide the study base for uniquely large population-based prospective studies on cancer. Define and implement a European Quality Standard for biobanking. Define and promote the implementation of integrity-proof methods for biobank-based research involving well defined and secure third party code-keeping systems. Enable large-scale, population-based research on: a) evaluation of cancer treatment and role of molecular markers in treatment selection; b) identification and evaluation of genetic markers associated with increased cancer risk using over-generation linkages; c) exploration and evaluation of intrauterine exposures associated with increased cancer risk using overgeneration linkages; d) design of optimal strategies for cancer prevention and its evaluation. Establish a Europe-wide network for spreading the awareness of possibilities and best practice quality standards for biobank-based research.
Background
Longitudinal studies nested in biobanks enable more reliable and efficient study designs, both for design and evaluation of cancer treatment and cancer prevention as well as for exploring and evaluating etiologic hypotheses. However, several prerequisites apply: There must exist very large-scale biobanks with several decades of follow-up. It must be possible to link biobanks with quality-assured populationbased cancer registries to enable population-representative studies with minimal case ascertainment bias. Important problems regarding overview, accessibility, quality control, phenotypic characterisation, efficiency and avoiding risks for violation of personal integrity must be addressed.
The participants
The present network has linked large biobank projects with up to 30 years of follow-up and >60 000 prospectively occurring cancer cases and cancer registries with >40 years of population-based registration. There are 19 partners in the project from nine European countries, including e.g.sevencancer registries,20 biobank projects and a number of platforms for advanced technological analysis of biobank samples.
The samples in the prospective research biobanks are aliquoted into color-coded tubes (buffy coat, EDTAplasma, heparinplasma and so on).
The freezer facility of the Medical Biobank in Ume
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Coordinator
Prof. Dillner, Joakim Lund University Department of Medical Microbiology Malomo University Hospital Entrance 78, 205 02 Malmo, Sweden Phone: + 46 40 338126 Fax: + 46 40 337312 E-mail: joakim.dillner@mikrobiol.mas.lu.se
Partners
Prof. Hakulinen,Timo Finnish Cancer Registry Helsinki, Finland Dr Thoresen, Steinar Kreftregisteret/The Cancer Registry of Norway Oslo, Norway Prof. de Villiers, Ethel-Michele Deutsches Krebsforschungszentrum Angewandte Tumorvirologie/Tumorvirus-Charakterisierung Heidelberg, Germany Prof. Lenner, Per Ume Universitet Institutionen fr Strlningsvetenskaper Onkologi, Ume, Sweden Prof. Jellum, Egil The Norwegian Cancer Society Institute of Clinical Biochemistry Oslo, Norway Prof. Hemminki, Kari Karolinska Institutet Department of BioSciences Huddinge, Sweden Prof. gmundsdttir, Helga M. Icelandic Cancer Society Molecular and Cell Biology Research Laboratory Reykjavik, Iceland Dr. Koskela, Pentti National Public Health Institute Department of Microbiology Laboratory of Prenatal Serology (Finnish Maternity Cohort serum bank) Oulu, Finland Prof. Bartram, Claus R University Hospital Heidelberg Institute of Human Genetics Heidelberg, Germany
Prof. Garnett, Geoffrey Imperial College of Science,Technology and Medicine Dept. Infectious Disease Epidemiology Faculty of Medicine St Marys Hospital London, United Kingdom Dr Lehtinen, Matti University of Tampere Public Health School and Medical School Tampere, Finland Prof. De Paoli, Paolo Centro di Riferimento Oncologico Department of Laboratory Medicine Laboratory of Microbiology Aviano, Italy Dr Houlston, Richard Section of Cancer Genetics Institute of Cancer Research Sutton, Surrey, United Kingdom Dr. Grzybowska, Ewa Centre of Oncology M. Sklodowska-Curie Memorial Institute Branch Gliwice Department of Tumour Biology Cancer Genetics Laboratory Gliwice, Poland Dr Marc Arbyn Scientific Institute of Public Health Unit of Epidemiology I.P.H. Brussels, Belgium Prof. Buntinx, Frank Limburgse Kankerstichting Limburg Cancer Registry (LIKAR), Hasselt, Belgium Prof. Lve, Arthur Landspitali University Hospital Department of Medical Virology Landspitali University Hospital Reykjavik, Iceland Hansson, Mats G. Uppsala University Dept. of Public Health and Caring Sciences Uppsala, Sweden
Acronym: CCPRB Project number: LSHC-CT-2004-503465 EC contribution: 6 050 000 Instrument: Network of Excellence Duration: 60 months Starting date: 01/06/2004
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eTUMOUR
Web-accessible MR decision support system for brain tumour diagnosis and prognosis, incorporating in vivo and ex vivo genomic and metabolomic data
Summary
The lifespan of the European population is increasing and, accordingly, diseases that become prevalent in old age, such as brain tumours, will afflict a larger percentage of this population. In addition, brain tumours are now one of the leading causes of death from cancer: the first in children under the age of 15 and the second from age 15 to 34.Brain tumours do not have a lifestyle-associated etiology, and so prevention is not yet possible. Diagnosis and treatment of brain tumours is based on clinical symptoms, radiological appearance and often a histopathological diagnosis of a biopsy. The current gold standard classification of a brain tumour by histopathological analysis of biopsy is an invasive surgical procedure and incurs a risk of 1-2% morbidity, in addition to healthcare costs and stress to the patients. For tumours that evolve slowly in malignancy (e.g.pilocytic astrocytoma in children) repeated biopsy may not be advisable at all. On the other hand, diagnosis using Magnetic Resonance Imaging (MRI) is non-invasive, but only achieves 60-90% accuracy depending on tumour type and grade.Likewise,treatment response of histological or radiologically similar tumours can vary widely,particularly for childhood tumours. Therefore, there is a need to improve brain tumour classification, and to provide noninvasive methods for brain tumour diagnosis and prognosis, to aid the patient management and to have a personalised treatment. Two molecular techniques are available to address these needs. Magnetic Resonance Spectroscopy (MRS) which can provide metabolic information on tissue either in vivo (non-invasive) or ex vivo (biopsy) and more recent DNA microarray analysis can determine tumour phenotype from gene expression profiles and genotype.The aim of eTUMOUR project is to coordinate European health care professionals with a validated Decision Support System (DSS) for noninvasive diagnosis of brain tumours, and the monitoring of tumour progression, and response, for future new therapies.This DSS product is based in an improved classification of brain tumours using molecular technologies such as Genomic and Metabolomic whose contributions will provide new knowledge of brain cancer biochemistry which could
be used for developing new bio-markers for a more precise diagnosis and for developing more selective and appropriated treatments. A particular and important feature of eTUMOUR is the quality control and validation system enclosed in the project that ensures the quality and efficacy of the final products.This European consortium is unique and we are not aware of any similar system being developed anywhere else worldwide.
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Coordinator
Prof. Celda, Bernardo University of Valencia Spain E-mail: bernardo.celda@uv.es Project web-site: http://www.uv.es/etumour, http://www.etumour.net Key words: DNA, micro-arrays, HR-MAS of biopsies, DSS, GUI, Molecular Imaging
Partners
Universitat Autnoma de Barcelona, Spain St Georges Hospital Medical School, London, United Kingdom University Medical Centre Nijmegen,The Netherlands Stichting Katholieke Universiteit,The Netherlands INSERM U594, France INSERM U318, France MICROART, S.L., Spain Hospital San Joan de Deu, Spain. Pharma Quality Europe, s.r.l. Italy Hyperphar Group SpA. Italy Katholieke Universiteit Leuven, Research & Development, Belgium Siemens AG, Medical Solutions, Germany SCITO S.A., France Universidad Politcnica de Valencia, Spain Deutsche Krebsforschungszentrum Heidelberg, Germany BRUKER BIOSPIN SA, France Institute of Child Health, University of Birmingham, United Kingdom FLENI, Argentina Medical University Lodz, Poland
Acronym: eTUMOUR Project number: LSHC-CT-2004-503094 EC contribution: 7 499 982 Instrument: Integrated Project Duration: 60 months Starting date: 01/02/04
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TRANSBIG
Translating molecular knowledge into early breast cancer management: building on the Breast International Group (BIG) network for improved treatment tailoring
Summary
The key to individualising treatment for cancer lies in finding a way to quickly translate the discoveries about human genetics made by laboratory scientists in recent years into tools that physicians can use to help make decisions about the way they treat patients.This area of medicine that links basic laboratory study to the treatment of patients is called translational research. TRANSBIG has been created as a multidisciplinary network of excellence devoted specifically to this type of research in breast cancer. TRANSBIG is a research network of 39 world-class institutions in 21 countries. Each participating organisation brings with it expertise that ranges from being specialised in cutting-edge biomedical technologies and cancer treatment programmes to lobbying governments on behalf of patient groups and supporting cancer societies. As a network, TRANSBIG will be dedicated to high-level collaboration that will contribute dramatically to advancing individualised treatment for breast cancer patients. Among its many strengths is the fact that it is linked to an already existing network of groups around the world that conduct clinical breast cancer research together the Breast International Group (BIG).BIGs 33 member organisations are active in 36 countries. The central secretariat is located in Brussels, and will coordinate the activities of both TRANSBIG and BIG. By linking the two networks and by benefiting from a central coordinating body, the fragmentation currently existing in the field will be reduced,and translational research in Europe will be strengthened and accelerated. New technologies will only gain acceptance by physicians and patients after first being validated in large, independent clinical trials. Microarray technology has enabled scientists to determine the signature of individual tumours,but it must be proven that this information is more reliable than existing methods for determining how to best treat individual patients. to develop and run a major clinical trial aimed at validating the hypothesis that understanding the genetic make-up (signature) of a tumour can lead to better targeted treatment.
Problem
Breast cancer is the most common cancer among women in developed countries, with one out of eight to ten women developing the disease in her lifetime.While incidence has steadily increased over the past decades, only recently has a slight decrease in deaths from breast cancer been noted, and that only in a few countries. Breast cancer is curable in about 70% of cases if diagnosed and treated early enough. But because of uncertainty over the best treatment in individual cases, many women receive chemotherapy or hormonal treatment after surgery based on the assumption that the risk is high that their breast cancer will recur. However, some women benefit significantly from such treatment and others only very little or not at all.The reason for this is because breast cancer is a disease that develops very differently in each woman. If individual tumours were better understood, physicians would be better able to make decisions about which treatments are best for individual patients and which patients need no further treatment after surgery at all. Presently it is estimated that about 12% to 20% of patients are over-treated,resulting in avoidable costs both to health services (financial) and patients (side-effects).
Technical approach
Although TRANSBIG will ultimately develop many projects,it will start with a clinical trial called MINDACT (Microarray for Node Negative Disease may Avoid Chemotherapy). This trial will compare two different ways of assessing the probability or risk that a womans breast cancer will come back. The traditional method is based on international guidelines and looks at specific characteristics such as the size of a patients tumour and whether the disease has spread to the lymph glands (nodes).The new method uses microarrays as a way of analysing the genetic components of a tumour. Specifically, traditional methods of assessing risk will be compared to a 70 gene tumour signature identified by a group of scientists at the Netherlands Cancer Institute that appears to predict very accurately whether a particular womans breast cancer will come back. MINDACT will involve 5000 women over a three-year period. Other cutting-edge techniques and technologies will be used in the project over time,and tumour and blood samples donated by patients will create an invaluable resource for further research that will help us to better understand and treat breast cancer.
Aim
to develop ways of individualising breast cancer treatment, so that treatment is tailored to the person receiving it. to integrate, strengthen and facilitate translational clinical breast cancer research in Europe and internationally by linking it to an existing network for clinical breast cancer trials (BIG).
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Expected results
Impact of MINDACT The TRANSBIG partners believe that the results of MINDACT will show that using the new technology to assess risk will result in fewer women being treated unnecessarily.This, in turn, will mean that fewer women will suffer from the unpleasant side-effects of chemotherapy. Not only will the overall quality of life of breast cancer patients be improved, but the health care costs associated with such cancer treatment will be reduced as well, thus providing a significant benefit to society. As the first project in TRANSBIG, MINDACT will also establish valuable resources for future research and establish links between research and biotechnology enterprises in order to develop further diagnostic tools that can be widely disseminated and easily used by scientists and physicians alike. Impact of TRANSBIG The long-term aim is to develop TRANSBIG into a permanent network for translational research that is complementary to the clinical work done by BIG.This guarantees a connection between what scientists learn in the laboratory and what physicians and patients decide together about treatments in the clinic. But TRANSBIGs reach will be wider than simply research. It will also be concerned with education through the provision of traineeships for young scientists and physicians and public education on the issues involved with genomics by working closely together with cancer societies and patient advocacy groups. By bringing together scientists, clinicians, and representatives from patient groups, cancer societies and industry,TRANSBIG will bring a coherence and synergy to breast cancer research that has previously not existed in Europe.
Coordinator
Piccart, Martine Jules Bordet Institute 1, rue Hger-Bordet 1000 Brussels, Belgium Phone: + 32 2 541 3526 Fax: + 32 2 541 3199 E-mail: transbig@bordet.be Key words: Breast cancer
Partners
Breast International Group (BIG-aisbl), Brussels, Belgium Institut Jules Bordet / Jules Bordet Instituut, Brussels, Belgium The Netherlands Cancer Institute, Amsterdam, The Netherlands Istituto Europeo di Oncologia - European Institute of Oncology, Italy Karolinska Institutet, Stockholm, Sweden University of Wales, Swansea, United Kingdom
The European Organization for the Research and Treatment of Cancer, Brussels, Belgium University of Glasgow, Glasgow, United Kingdom Universitaet Wien,Vienna, Austria Grupo Oncologico Cooperativo Chileno de Investigacion, Santiago, Chile Bank of Cyprus Oncology Centre, Nicosia, Cyprus Univerzita Karlova v Praze, Prague, Czech Republic Finsen Centre - Rigshopitalet, Copenhagen, Denmark Institut Gustave Roussy,Villejuif, France West German Study Group, Universitaetsklinikum Dusseldorf, Dusseldorf, Germany Klinikum der Johann Wolfgang von Goethe Universitaet, Frankfurt, Germany Technische Universitaet Muenchen, Munich, Germany Universitaetsklinikum Eppendorf, Hamburg, Germany National and Kapodistrian University of Athens, Athens, Greece St Vincents University Hospital, Dublin, Ireland Gruppo Oncologico Italiano di Ricerca Clinica, Parma, Italy Centre Hospitalier de Luxembourg, Luxembourg Universiteit Maastricht, Maastricht,The Netherlands Medical University of Gdansk, Gdansk, Poland Portuguese Institute of Oncology Francisco Gentil, Porto, Portugal N. N. Blokhin Cancer Research Centre, Moscow, Russia Institute of Oncology, Ljubljana, Slovenia Institute of Oncology of Southern Switzerland Mendrisio, Switzerland Marmara University Medical School Hospital, Istanbul, Turkey Federation of European Cancer Societies, Brussels, Belgium Europa Donna The European Breast Cancer Coalition, Milan, Italy Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal GSF Forschungszentrum fuer Umwelt und Gesundheit, Munich, Germany Agendia,Amsterdam,The Netherlands International Institute for Drug Development, Brussels, Belgium Fundacion Institut per la Recerca Vall dHebron, Barcelona, Spain Grupo Espaol de Estudio,Tratamiento y otras Estrategias Expirementales en Tumores Slidos, Madrid, Spain Swiss Institute of Bioinformatics, Lausanne, Switzerland University of Oxford, Oxford, United Kingdom
Acronym: TRANSBIG Project number: LSHC-CT-2004-503426 EC contribution: 7 000 000 Instrument: Network of Excellence Duration: 60 months Starting date: 01/03/2004
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European LeukaemiaNet
Strengthen and develop scientific and technological excellence in research and therapy of leukaemia (CML,AML,ALL, CLL, MDS, CMPD) by integration of the leading national leukaemia networks and their interdisciplinary partner groups in Europe
Summary
Leukaemias are a challenge to society and a cost factor because of their frequency in all age groups.They also serve as a model for a variety of diseases and possess exemplary relevance for basic research and patient care. Leukaemia research and therapy have achieved high standards and even a leading position in several European countries with regard to clinical trials,standardisation of diagnostics and molecular studies of signal transduction and gene expression. A true European world leadership, however, has not been accomplished yet due to national fragmentation of leukaemia trial groups,diagnostic approaches and treatment research activities and a need for central information and communication structures. guidelines), industry and SMEs across Europe to form a cooperative network for advancements in leukaemia-related research and health care. Integration will be supported by central information, communication, education and management structures. Other goals are to intensify target and drug discovery, to shorten the time period to clinical translation, to apply advanced genomics, telematics and biotechnology to therapeutic progress and to promote research relevant also for solid cancers by large clinical trials. Furthermore, meta-analyses of specific subaspects, elaboration of prognostic scores, recognition of gender-specific differences, creation of uniform data sets for trials and registration, introduction of standards for diagnostics and treatment and development of evidence-based guidelines will be promoted throughout Europe.The proposed network will have the expertise and critical mass for European added value and world leadership. It will structure European research durably, spread European scientific excellence in the field of leukaemias and can start immediately. The 78 leukaemia trial groups and their 83 interdisciplinary partner groups representing several thousand participating centres and ten thousands of study patients treated within the trial groups form the backbone of the network. The network consists of 18 work packages. Of these, six deal with the various diseases (AML, ALL, CLL, CML, MDS, CMPD) and represent sub-networks on their own. Nine work packages represent interdisciplinary platforms which provide the support and research expertise required for high quality networking and excellence. Three core work packages provide central communication and management services for the whole network. The integration and interdisciplinary cooperation brings together 116 participants and approximately 900 researchers from 22 countries. The network will overcome national fragmentation and provide the critical mass to achieve research and treatment goals that cannot be achieved by single European countries.
Aim
Multiple drug resistant bacteria are a major threat to human health and a significant burden on already stretched medical budgets.This threat is predicted to increase in severity, and remedial actions of reducing antibiotic use in animal husbandry and limiting current prescribing activities for non-lethal human disease are both unlikely to reduce the danger in the short-term. Of major concern are antibiotic-resistant nosocomial infections.The economic and societal costs of these hospital-acquired infections are enormous: the UK National Health Service has estimated an annual cost of 1.5 billion for extra patient care and that 5000 deaths result each year. In addition, the incidence of infection by multiple drug resistant strains of Mycobacterium tuberculosis, the causative agent of the tuberculosis, is rapidly increasing, particularly among the disadvantaged in society. Investment in R&D into antibiotic discovery by the major pharmaceutical companies has declined dramatically in the last 15 years as a perception has taken hold that easily obtained natural products may have been fully exploited. Hence conventional screening of natural products for new drugs is no longer considered economically worthwhile. Unfortunately, the downturn in drug discovery has coincided with a dramatic worldwide increase in the incidence of resistance to all the antibiotics currently used in medicine. The objective is to integrate the 78 leading leukaemia trial groups (chronic myeloid leukaemia (CML), acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic lymphoid leukaemia (CLL), myelodysplastic syndromes (MDS), chronic myeloproliferative disorders (CMPD)), their 83 interdisciplinary partner groups (diagnostics, treatment research, registry,
Expected results
1. Establishment of central information and communication structures to create networks and platforms for all leukaemias and their interdisciplinary partners. Integration is mediated by exchange of current trial protocols and procedures, information on participating centres and recruited patients and employment of uniform common data sets for comparable study outcomes and evaluations provided by the biometrical center (WP 17).This objective will be achieved through central services: Network Management Center (NMC, WP 1), European Leukaemia Information Center (ELIC,WP 2) and Central
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Information and Communication Services (CICS,WP 3).The central service groups benefit from a three years' experience in similar tasks for the German Competence Network for Acute and Chronic Leukaemias funded by the German Ministry for Education and Research (BMBF) and provide the basis for a head start of the network. These groups will also provide training programmes, workshops, symposia, exchange of researchers and information programmes, thereby spreading excellence to health care personnel, researchers and to other countries not yet participating in the network.With the support of NMC (WP 1) the network will be managed in a two-layer networking organisation. Clinical trial groups for each leukaemia and their interdisciplinary partner will form their own European subnet organizations with coordinators, steering groups and management structures. These subnets and platforms will then be integrated in the European Leukaemia Network which will conduct the integrated research programme detailed below. The network will be managed by the Network Coordinator (NC), the Scientific Network Manager (SNM) and the Steering Committee (SC) consisting of the coordinators (=Lead participants) of the work packages (WP). The University of Heidelberg will provide the expertise for financial, legal and contractual management. 2. Set-up of European networks for each leukaemia and related syndrome. These networks will comprise the national trial groups for each leukaemia and represent the first stage of networking and European integration. 3. Set-up of European platforms for each interdisciplinary specialty. These platforms are sub-networks of excellence of diagnostic, therapeutic and biometric research groups on their own and constitute interdisciplinary partners enabling the clinical trial groups to achieve the high quality patient care and research required for European leadership. 4. Performance of clinical trials (all leukaemias). Employing uniform common data sets the trial groups will continue their current trials funded by alternative sources and will start new trials using diagnostic standards established by the diagnostic platforms (WPs 10-13) and employing new drugs provided by pharmaceutical companies and/or the sub-network on treatment research/new targets/ new drugs (WP 16). Criteria for accreditation of trials will be set up. Lung infection and inflammation is a growing problem within all states of the EU, and the infections are routinely treated with antibiotics. The pharmaceutical industry is interested in the development of protein therapeutics, which can be used as alternatives to antibiotics.There is a relatively fragile protective barrier, the alveolar lining layer, which controls the interaction between the atmosphere and the lung.The film, known as lung surfactant, plays two important
roles, prevention of lung collapse during respiration and provision of a first line of defence against the extremely varied range of particles, allergens and microbes that are present in the environment. The lung surfactant is a surface-active mixture of phospholipids and four main surfactant proteins SP-A, SP-B, SP-C and SP-D.The SP-B and SP-C proteins are small, highly hydrophobic, polypeptides, which are strongly associated with the phospholipid portion of the surfactant, whereas SP-A and SP-D are large (approximately 600kDa) and complex, disulphide-bonded, proteins of a more hydrophilic nature.They can bind, via their lectin domains, to arrays of carbohydrate structures on the surfaces of pathogenic microbes and to glycosylated allergens, thus initiating defence against a range of viral, fungal and bacterial lung infections and modulating allergic reactions.There is evidence of lowered levels of SP-A, and SP-D, in the lung surfactant of a growing number of types of infectionor allergy-mediated lung inflammation, which strengthens the case for testing the use of recombinant forms of these proteins as therapeutic alternatives to antibiotics. 5. European Registry (all leukaemias). A European registry will allow to determine incidence and disease patterns across Europe including gender, age and ethnic differences, investigate familiar aggregations, overlap syndromes or precursor conditions, explore risk factors associations and differences in gene environment interaction, using data from cytogenetic analyses (WP 11) and genomic profiling (WP 13),perform quality of life assessments, recognize sub-entities on the basis of cytogenetic or gene profiling information, follow-up patients for the development of prognostic
Geographic distribution of lead participants and participants representing national study groups comprising more than 1,000 centers in 22 countries
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scores for old and new therapies and determine proportions of patients in individual countries treated on specific protocols or with specific therapies e.g. SCT (WP 14).The registry will be run by the expert group Biometry for Registry, Epidemiology, Metaanalyses and Prognosis (WP 17). This group has gained a long-standing broad experience in collecting data, performing meta-analyses and establishing prognostic scores. The database established by the network will have far-reaching implications for research and public health planning far beyond the period of EC funding. 6. Standardisation Standardised and quality controlled diagnostic procedures and therapies constitute the basis for improvements of clinical outcomes. This concerns all diagnostic approaches such as morphological diagnosis of blood and marrow cells (WP 10), cytogenetics (WP 11), detection of minimal residual disease (WP 12) and gene expression profiling (WP 13) as well as therapies such as transplantation,anti-infection prophylaxis and treatment and the testing of new drugs in phase I/II trials (WP 14-16).The establishment of standards for a wide spectrum of diagnostic and therapeutic applications will raise the quality of research and patient care beyond the period of EC funding and will predictively have a profound impact on outcome as measured by prolongation of life and cure rates across Europe.
7. Metaanalyses and guidelines Whenever randomised trials are available for analysis (mostly CML and AML), meta-analyses will be performed and published (WP 17). On the basis of meta-analyses,evidence-based guidelines (WP 18) will be worked out and used for the improvement of patient management and for educational purposes (training programmes, workshops in associated countries, exchange of researchers and physicians for training purposes).Meta-analyses will be also performed on combined data sets with rare subtypes of leukaemias (WP6).
Network Structure: The different platforms are grouped into workpackages (WP). Central services: WP 1: Network Management Center (NMC),WP2: Leukemia Information Center (ELIC),WP3: Central Information and Communication Services (CICS). Clinical trial platforms:WP4: CML,WP5: AML,WP6: ALL,WP7: CLL,WP8: MDS;WP9: CMPD. Diagnosis/Follow-up: WP10: Diagnostics;WP11: Cytogenetics;WP12: MRD;WP13: Gene Profiling. Treatment Research:WP14: Stemcell Transplantation;WP15: Supportive Care, Anti-infection Prophylaxis and Treatment;WP16:Treatment Research / Drug Development. Registry/Education:WP 17: Biometry of Registry, Epidemiology, Metaanalyses and Prognosis;WP18: Guidelines.
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Coordinator
Prof. Hehlmann, Rdiger III. Medizinische Universittsklinik Ruprecht-Karls-Universitt Heidelberg Wiesbadener Str. 7-11 68305 Mannheim, Germany Phone: + 49 621 383 4115 Fax: + 49 621 383 4201 E-mail: R.Hehlmann@urz.uni-heidelberg.de Project web-site: http://www.leukaemia-net.org Key words: leukaemia, CML, AML, ALL, CLL, MDS, CMPD
Universitt Kln, Germany Stichting Katholieke Universiteit, Univ. Medical Center Nijmegen,The Netherlands Azienda Ospedaliera - Ospedali Riuniti di Bergamo, Italy IRCCS Policlinico S. Matteo, Italy Universit Henri Poincar Nancy 1, France St. Marien-Krankenhaus Siegen gem. GmbH, Germany Medizinische Unversitt Wien, Austria Philipps-Universitt Marburg, Germany King's College London, United Kingdom Imperial College London, United Kingdom University of Basel, University Hospitals - Switzerland Universitt Leipzig , Germany Karolinska Institutet, Sweden Eberhard-Karls Universitt Tbingen, Germany Uniersity of Newcastle upon Tyne, United Kingdom Association pour la Recherche sur les Transplantations Medullaires, France
Partners
Universittsklinikum Frankfurt, Germany Ludwig-Maximilians-Universitt Mnchen, Germany Uppsala Universitet, Sweden Universita di Bologna - Unita Complessa di Istituti di Cardiologia ed Ematologia, Italy Universit de Poitiers, France Ruprecht-Karls-Universitt Heidelberg, Germany Universittsklinikum Mnster, Germany University of Wales, College of Medicine, United Kingdom Fundacion Hospital Universitario La Fe, Spain Les Hospices - CHUV - Switzerland Dipartimento di Biotecnologie Cellulari ed Ematologia, Universita degli Studi di Roma La Sapienza, Italy Leiden University Medical Center,The Netherlands Institut Pasteur, France Universitt Ulm, Germany
Acronym: European LeukaemiaNet Project number: LSHC-CT-2004 503216 EC contribution: 6 000 000 Instrument: Network of Excellence Duration: 60 months Starting date: 01/01/2004
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DNA METHYLATION
Epigenetic profiling of breast cancer: prognostic and therapeutic applications

Summary
A key clinical question in the management of primary breast cancer concerns the assessment of information provided by risk factors measured in blood and tissue that support the choice of an optimal adjuvant treatment regimen for the individual patient. The basic understanding of breast cancer initiation and progression is still far from being understood. Apart from that, we will need to develop highly reliable methods to classify breast cancer patients in different risk groups, based on their detailed tumour characteristics. Cancer is a genetic as well an epigenetic disease. A prominent epigenetic alteration is DNA-methylation in the promoter region of the gene that prevents the gene to be expressed.Our translational project uses newly developed state-of-the-art DNA methylation approaches that recently have become available through partners of this consortium.The aim of the project is to develop prognostic and predictive DNA methylation profiles for breast cancer patients. The fifth base in the genome: Methylation of the carbon 5 position is the epigenetic modification in the mammalian genome that contributes to cancer Epigenomics AG, Berlin.
Problem
Breast cancer is the leading malignancy in women and a leading cause of death.The mortality rate has slightly decreased over the past few years, but statistic tends indicate that the incidence is rising further due the aging of the population.The high importance of the necessity of improved breast cancer diagnosis and therapy is without any doubt. Markers that allow better targeting of available therapies to particular patients will most likely improve outcome in cancer in the future. Indeed, the dilemma of optimal treatment of primary breast cancer is complex for both patients with primary breast cancer and for patients with recurrent disease (metastases). To enable and allow tailored therapy concepts that take the individual tumour biology into account, new and specific tumour-associated factors are needed that guide the physician in the prediction of the patient's prognosis and of therapy response. Even though enormous efforts have been put into the identification of prognostic and predictive factors over the years the successful identification of strong markers has been limited.This
is due to imperfect technologies, limited size and heterogeneity of patient cohorts studied and lack of reproducibility and uniform assay methodologies as well as quality assurance programs.
Background on DNA methylation in cancer

DNA methylation occurs only on cytosines, and methyl-cytosine is considered the fifth base (Figure 1).In cancer,DNA methylation shifts towards the regulatory regions of genes resulting in silencing of tumour suppressor genes. Promoter DNA methylation is a booming field in cancer biology since it has become apparent that this epigenetic type of gene regulation contributes to many aspects of cancer biology, such as tumour initiation, tumour aggressiveness, tumour metastasis, and tumour behaviour during systemic therapy.
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DNA methylation as diagnostics

Several properties make epigenetic changes at the level of the DNA attractive as diagnostic targets. DNA methylation is very stable and localised; it can be turned into genetic information and subsequently amplified by classic PCR. Finally, methylation detection is feasible in fixed, paraffin-embedded material.These features allow for sensitive and quantitative detection and rapid transfer of a diagnostic test to DNA methylation as molecular switch: clinical routine. Furthermore, Methylation of cytosine in the regulatory region of a gene turns it ON or OFF.This way it consince DNA methylation regulates tributes to the cancer phenotype with respect to aggressiveness and therapy responsiveness.The gene expression and results from project aims to identify the key molecular switches. Since the simple nature of the change, methya simple change, a methylation on lation or not, it can be treated as binary information Epigenomics AG, Berlin. a cytosine residue or not, it can be considered as a binary genotypic change that is responsible for the other types of systemic therapy.To identify the markers genome-wide observed phenotypic difference (Figure 2). Although DNAhigh-throughput DNA methylation screening will be performed on methylation markers have not found their way to the clinic yet, well-defined breast tumour tissue banks (>20,000 tumour tissue they could be important and powerful diagnostic or predictive samples) with complete computerized follow-up information on markers not far ahead. patient's course of the disease and treatment response.We intend to identify DNA methylation markers that predict prognosis and therapy Aim success. The 9 participating centres contribute complementary proprietary technical expertise, large and well-documented tissue The key activity of this project is to identify and validate DNA resources, and extensive clinical knowledge.To maximize the chances methylation markers with clinical value. The project addresses the to successfully identify specific risk-associated targets for tumour clinical need to come to tailored treatment of breast cancer patients, aggressiveness and effectiveness of systemic endocrine and of whom a large proportion is over-treated, or would benefit from chemotherapy,DNA is prepared from carefully selected tumours from
Binary epigenetic predictor: Predictive DNA methylation patterns identified during this project and indicated by the barcode here can guide the clinician to decide whether to treat or not the treat and to determine the best type of treatment for the individual patient Epigenomics AG, Berlin.
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the large tissue collectives that are available through members of this consortium.After the identification of potential target genes for some of the major clinical questions regarding breast cancer prognosis and therapy prediction, validation steps are carried out. The latter also involves biochemical validation of mRNA and protein expression of the differentially methylated genes, and clinical validation of the newly discovered targets in large numbers of tumours. The ultimate goal of the project is to improve breast cancer prognosis and treatment in the European Community and beyond and give the European Union the lead in this important field of cancer diagnostics.
Prof. Dr. Nils Brnner Royal Danish Veterinary and Agriculture University Institute of Pharmacology and Pathobiology Frederiksberg C, Denmark Dr. Fred CGJ Sweep Department of Chemical Endocrinology University Medical Center Nijmegen Nijmegen,The Netherlands Dr. Sabine Maier Epigenomics AG Berlin, Germany Dr. Frdrique Spyratos Centre Ren Huguenin Laboratoire d'Oncobiologie St-Cloud, France
Expected results and potential applications

The prime spin-off of our current project is to provide a major refinement of breast cancer classification allowing accurate prediction of patient prognosis and response to therapy based on newly identified DNA methylation markers as exemplified in Figure 3. The intellectual property generated during this project will be patented. We expect the diagnostic tests to be used for clinical decisions about the choices of treatment.
Coordinator
Dr. John A. Foekens Department of Medical Oncology Erasmus MC Rotterdam Josephine Nefkens Institute, Rm BE426 Dr. Molewaterplein 50 3015 GE Rotterdam,The Netherlands Phone: +31 10 4088369 Fax: +31 10 4088365 E-mail: j.foekens@erasmusmc.nl Project web-site: http://www.erasmusmc.nl/interne_oncologie/FP6/ Key words: breast cancer, DNA methylation, diagnostic markers, prognosis, chemotherapy, endocrine therapy.
Dr.Tanja Cufer Department of Medical Oncology Institute of Oncology Ljubljana, Slovenia Dr. Joe Duffy National University of Ireland Nuclear Medicine Department St.Vincent's University Hospital Dublin, Ireland Dr. Serenella Eppenberger-Castori Prof. Dr. Urs Eppenberger Stiftung Tumourbank Basel Riehen, Switzerland
Partners
Prof. Dr. Manfred Schmitt Dr. Nadia Harbeck Department of Obstetrics and Gynecology Technische Universitt Mnchen Klinikum rechts der Isar Munich, Germany
Acronym: DNA METHYLATION Project number: LSHC-CT-2003-504586 EC contribution: 2 533 758 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/01/2004
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European MCL Network
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European Mantle Cell Lymphoma Network:Translation evaluation of molecular prognostic factors and pharmacogenomics in European interdisciplinary collaboration
Summary
Mantle cell lymphoma (MCL) is a subtype of malignant lymphoma with an especially poor prognosis. Recently, a European MCL Network of clinicians, basic scientists and pathologists has been established to investigate the clinical as well as molecular aspects of MCL. In previous clinical trials,the superiority of innovative treatment options (high dose therapy,combined immuno-chemotherapy) has been confirmed,and cell proliferation has been identified as the most important prognostic factor. Based on these extensive prerequisites, we have initiated a translational approach to evaluate innovative treatment options (like immuno-chemotherapy, radioimmunotherapy, high dose consolidation and molecularly targeted approaches) and molecular prognostic markers in prospective randomised studies.All study cases are subjects of innovative molecular analyses and continuous detection of minimal residual disease.This translational approach will not only lead to more effective therapeutic strategies based on the molecular profiling but also pave the way to molecular targeted treatments.
Expected results
1. Prospective evaluation of combined immunochemotherapy and myeloablative consolidation in patients <65 years: R-CHOP followed by myeloablative consolidation vs. R-CHOP/R-DHAP followed by high dose Ara-C therapy 2. Prospective evaluation of combined immunochemotherapy and different maintenance strategies in patients >65 years: R-CHOP vs. R-FC followed by IFN vs. Rituximab maintenance; 3. Regular histomorphological panel review of study cases (subtyping according to cytological criteria); 4. Prospective evaluation of a panel of proliferation-associated and new oncogenic markers (immuno-histochemistry); 5. Prospective evaluation of MRD detection (PCR, FACS, FISH) in the patient cohort of the European MCL Network; 6. Prospective evaluation of the proliferation-associated gene signature in the patient cohort of the European MCL Network (RNA array).
Problem
Mantle cell lymphoma (MCL) is a distinct, clinically very aggressive subentity of malignant lymphoma with a median survival of three years. However, a small subset of patients represents long-term survivors. So far, the discriminative power of different prognostic parameters has been limited and did not allow the reliable identification of the individual patient's risk profile. Thus, a better understanding of the underlying molecular mechanisms is eagerly warranted.
Aim
Based on the previously established European MCL Network of clinicians, basic scientists and pathologists and the recent development of innovative molecular techniques (matrix CGH,RNA array chips,RQPCR, proteomics), we are performing a global approach to investigate innovative treatment options of MCL and evaluate new predictive (pharmacogenomics, minimal residual disease) and prognostic molecular markers (genomic alterations, RNA/proteome profiles) in controlled prospective studies. This translational approach of the European MCL Network will not only lead to more individualised therapeutic strategies based on the molecular risk profile but will also finally elucidate the way to future molecular targeted treatment options in a subtype of malignant lymphoma with an otherwise dismal clinical outcome.
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Malignant lymphoma is currently the fourth most frequent malignant disease and displays the highest increase in annual incidence of all hematological neoplasias. In this regard, the exploration of innovative treatment strategies and evaluation of prognostic markers in the rather rare disease of mantle cell lymphoma is also a model disease for much more frequent diseases which have a profound impact on the public health system as well as the general society.The prospective studies of the European MCL Network studies will enable us to gain a deeper understanding of the pathophysiological network of cell programme regulation in malignant lymphoma. In addition, applying this multivariate procedure, the critical biological players of malignant transformation will be identified which may represent the suitable target genes of future treatment strategies in a disease with otherwise dismal prognosis. Moreover, this collaboration of outstanding clinical as well as molecular scientists will be a paradigm for other fields of biological research interlinking clinical and basic science as well as scientific excellence from all over Europe.
Coordinator
Dr Dreyling, Martin Wolfgang Hiddemann University Hospital Grohadern Ludwig-Maximilian-University Munich Dept. of Medicine III Marchioninistr. 15 81377 Mnchen, Germany Phone: + 49 89 7095 2202 Fax: +49 89 7095 2201 E-mail: martin.dreyling@med.uni-muenchen.de Project web-site: www.lymphome.de Key words: mantle cell lymphoma, therapy, molecular risk factors, minimal residual disease (MRD), pharmacogenomics, RNA array profiling, proteomics
Partners
Dr Smedegaard, Niels Andersen Rigshospitalet University Hospital Copenhagen Dept. of Hematology Copenhagen, Denmark Prof. Campo, Elias Hospital Clinic University of Barcelona Hematopathology Section Laboratory of Pathology Barcelona, Spain Prof. van Dongen, J J M Erasmus University Medical Center Rotterdam Department of Immunology Rotterdam,The Netherlands Prof. Kluin, Philip M Academic Hospital Groningen Dept. of Pathology and Laboratory Medicine Groningen,The Netherlands
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Prof. van Krieken, Johannes H J M Stichting Katholieke Universiteit University Medical Centre Nijmegen Department of Pathology Nijmegen,The Netherlands Prof. Macintyre, Elizabeth Assistance Publique-Hopitaux de Paris Hopital Necker-Enfants Malades Hematology Laboratory Paris, France Dr Martinez-Climent, Jose Angel Fundacion Para la Investigacion Medica Aplicada (FIMA) Centro para la Investigacion Medica Aplicada (CIMA) Laboratorio de Oncologia Molecular 108 Universidad de Navarra Pamplona, Spain Prof. Meitinger,Thomas GSF National Research Institute for Environment and Health Institut fr Humangenetik Ingolstdter Neuherberg, Germany Dr Ott, German / Dr Rosenwald, Andreas Bayerische Julius-Maximilian-Universitt Wrzburg Pathologisches Institut Wrzburg, Germany Prof. Parwaresch, Reza / Dr Klapper,Wolfram Universittsklinik Kiel Institut fr Hmatopathologie Wrzburg, Germany Dr Pott, Christiane University Hospital Schleswig-Holstein Campus Kiel II. Med. Klinik und Poliklinik Kiel, Germany Dr Ribrag,Vincent Institut Gustave Roussy, Sce d'Hematologie Villejuif, France
Prof. Salles, Gilles Universite Claude Bernard Lyon-1 Centre Hospitalier Lyon-Sud Service dHematologie Pierre-Benite, France Prof. Schlegelberger, Brigitte Medizinische Hochschule Hannover Inst. fr Zell- und Molekularpathologie Hanover, Germany Dr Siebert, Reiner University Hospital Schleswig-Holstein Campus Kiel Institute of Human Genetics Kiel, Germany Dr Stilgenbauer, Stephan Universittsklinikum Ulm Innere Medizin III Ulm, Germany Dr Thieblemont, Catherine / Dr Callet-Bauchu, Evelyne Universite Claude Bernard Lyon-1 Equipe Associee Pathologie des Cellules Lymphoides Pierre-Benite, France Dr Trnny, Marek Univerzita Karlova v Praze (Charles University of Prague) 1st Dept. of Medicine 1st Faculty of Medicine Praha, Czech Republic Dr Walewski, Jan Maria Sklodowska-Curie Memorial Cancer Center Institute of Oncology Warszawa, Poland
Acronym: European MCL Network Project number: LSHC-CT-2004-503351 EC contribution: 2 493 900 Instrument: Scientific Targeted Research Project Duration: 36 months Starting date: 01/07/2004
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BRECOSM
Identification of molecular pathways that regulate the organ-specific metastasis of breast cancer
Summary
The objectives of this project are to identify genes, proteins and molecular pathways involved in regulating the metastasis of breast cancer to specific organs.To achieve these objectives we will use a combination of gene expression profiling, bioinformatic analysis, histology of human female breast cancer samples, genetic manipulation of transplantable tumor cells and transgenic mouse technology.In addition to finding new genes, we aim to analyse to what extent genes already known to play a role in breast cancer metastasis specify which organs breast tumors metastasise to.We will also establish how the currently known genes that are associated with breast cancer dissemination and the new ones we identify fit together into pathways that regulate organ-specific metastasis.These findings will be coupled with the analysis of clinical trials in which participants in this consortium are involved.Further deliverables include the development of improved animal models for the study of breast cancer metastasis, and the development of diagnostic methods for determining whether primary tumours already have metastatic potential. Together, the work packages in this project will establish a pipeline of activities that unite basic research into the organ-specific metastasis of breast cancer with target validation and clinical application. improved clinical decision-making, prognostic evaluation and therapy in breast cancer. Mammary tumor showing the lymphatic vessels that impinge upon the tumor (blue staining). Increased lymphatic vessel density promotes metastasis to regional lymph nodes
Aims
to identify genes that are specifically up- or down-regulated in breast cancer metastases in specific organs; to identify gene expression signatures in primary breast tumours that predict metastasis to specific organs or predict the prognosis of ductal carcinoma in situ (DCIS); to determine whether genes already associated with breast cancer invasiveness and metastasis are expressed in metastases in all or only a subset of organs; to demonstrate whether genes found to be specifically expressed in breast cancer metastases to given organs play a functional role in organ-specific metastasis; to elucidate molecular pathways that regulate breast cancer metastasis to specific organs; to develop improved animal models for studying organ-specific metastasis of breast cancer; to produce a prototype microarray chip for diagnostic/prognostic evaluation; to apply the findings on organ-specific metastasis in the clinical setting.
Problem
Breast cancer is a major health issue and is highly gender relevant. It is the most often diagnosed female cancer, and the majority of cases are already invasive at diagnosis.More than 17% of cancer deaths result from breast tumours, making breast cancer a major societal problem. Treatment involves radical and disfiguring surgery, often with long-term side effects such as the development of lymphedema of the arm, and radiotherapy and chemotherapy,again associated with severe side effects. The effects of metastatic spread of the tumour cells and the formation of secondary deposits in a wide variety of organs are the cause of death due to breast cancer. Metastases to organs such as bone and brain are major causes of suffering in terminally ill patients. The incidence of breast cancer increases sharply between the ages of 30 and 50 meaning that many women in the prime of life are affected by this disease. Not only does this mean that many families are traumatised, but it also has severe economic consequences, removing economically active women from society. Further economic consequences arise as a result of the high health care costs associated with treating breast cancer patients. Clearly improvements in the treatment and management of breast cancer would have impact on both health and the economy.By analysing molecular mechanisms that regulate organ-specific metastasis in breast cancer, the BRECOSM project will identify tools that will contribute to
Expected results
The results of this project will begin to explain the molecular basis for organ-specific metastasis in breast cancer. This project will identify regulatory pathways and cellular events that coordinate organ-specific metastasis of breast cancers.Novel targets for therapy will thereby be identified. This project will identify gene expression signatures in tumours associated with metastasis to particular organs. This will be an important advance in understanding the underlying genetic changes that regulate organ-specific metastasis in breast cancer. This project will bring together European experts working on different aspects of the molecular basis of tumour metastasis.As a
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result of coordinated efforts, pathways that regulate metastasis to specific organs will be determined, and genes that play a functional role in organ-specific metastasis will be identified. This project will generate improved animal models for the further study of breast cancer metastasis to specific organs. This project will identify gene expression signatures in primary breast tumours that predict patterns of metastasis.The application of these findings will assist clinical decision making and prognostic evaluation.
Coordinator
Sleeman, Jonathan Forschungszentrum Karlsruhe Institut fr Toxikologie und Genetik Postfach 3640 76021 Karlsruhe, Germany Phone: + 49 7247 826089 E-mail: sleeman@itg.fzk.de Project web-site: http://itgmv1.fzk.de/itg/brecosm/brecosm.htm Key words: cancer, breast, metastasis, gene expression profiling
The gene expression signatures in primary tumours identified in this project that predict organ-specific metastasis and the prognosis of DCIS will have obvious potential for clinical application in diagnosis and prognostic assessment.Gene expression signatures in primary tumours associated with either organ-specific metastasis or progression of DCIS will be extensively validated retrospectively and as a prelude to introducing these gene expression signatures into clinical diagnosis and prognostic evaluation, we will perform prospective studies to demonstrate the efficacy of examining gene expression signatures in primary breast cancers for predicting the likelihood and location of metastases and the probability that DCIS will progress and metastasise after partial mastectomy. The prototype microarray chips we create based on gene expression profiles produced as part of this project will be applied in the clinical setting to investigate their diagnostic and prognostic value for breast cancer in a prospective study. This will constitute a major step towards exploitation of the results.It is also highly likely that genes are identified in this project will be candidate targets for the development of novel cancer therapies.The development of such therapies lies outside the time-frame and scope of the proposal. Wholemount staining of the epithelial ductal structure in a mouse mammary gland.The lymph nodes are also visible as densely-stained spheroidal structures.
Partners
Van Roy, Frans Department for Molecular Biomedical Research (DMBR) VIB - Ghent University, Ghent, Belgium Christofori, Gerhard Institute of Biochemistry and Genetics, Department of ClinicalBiological Sciences, University of Basel Basel, Switzerland Lukanidin, Eugene Danish Cancer Society, Institute of Cancer Biology Copenhagen, Denmark Thiery, Jean Paul CNRS UMR 144, Institut Curie, Cell Biology Department Paris, France Georg-Speyer-Haus Frankfurt am Main, Germany Nol,Agns Laboratoire de Biologie des Tumeurs et du Dveloppement Lige, Belgium Collard, John The Netherlands Cancer Institute, Division of Cell Biology Amsterdam,The Netherlands ten Dijke, Peter The Netherlands Cancer Institute Division of Cellular Biochemistry Amsterdam,The Netherlands Stauber, Roland Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Paul-Frankfurt am Main, Germany Zollo, Massimo TIGEM-Telethon Naples, Italy
Acronym: BRECOSM Project number: LSHC-CT-2004-503224 EC contribution: 3 430 273 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/05/2004
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MetaBre
Molecular Mechanisms involved in organ-specific Metastatic growth process in Breast Cancer

Summary
MetaBre is a EU-funded research project that aims to identify the underlying mechanisms that cause metastasis in breast cancer.There has been considerable success in the treatment of breast cancer in recent years,if detected in its early stages.However,breast cancers are very prone to metastasise, and cause secondary tumours in bone, liver, lungs, brain and lymph nodes. Once solid metastatic tumours are established, the likelihood of complete remission falls, and patients can suffer symptoms generated by metastases that affect quality of life. More than 200,000 women are diagnosed in Europe every year. Lifetime risk of developing breast cancer is 1 in 10. It is the leading cause of death in women between ages 35 to 55. Metastasis in breast cancer is a complex multistep process. Genetic changes in tumour cells give rise to aggressive metastatic cells, and these home in on specific organs because of a complex web of molecular and matrix interactions with the organ microenvironment. Understanding the key molecular mechanisms of these metastatic processes can lead to improvements in the prognosis and treatment of breast cancer patients. Main group, L to R: Roberto Buccione, Olivier de Wever, Pavel Gromov,Anna Teti, David Waltregny, Keltouma Driouch, Michael Baldwin,Akeila Bellahcene, Gabri van der Pluijm, Nadia Rucci, Philippe Clement-Lacroix, Sue Eccles, Marc Bracke, Rosette Lidereau,Vincent Castronovo,Angels Sierra, Ben-Tsion Williger, Rachel Klein, Rita Paro. Insets L to R: Lenaic Paon,Verena Collazo, Nick Henriquez Philippe Clezardin., Richard Bachelier, Philippe Pujuguet, Marcela Chavez, Maciej Ugorski,Anna Laskowska not pictured:,Thomas Landemaine
Expected results
MetaBre has research activities aimed at: gene profiling and proteomic analysis to identify new molecular targets functional analysis of new targets in in vitro and in vivo models
Aims
MetaBre will aim to discover new gene and protein markers that can be used for diagnosis as a signature of metastasis to specific organs, and also can be targets for therapy. To achieve this, the partners will analyse samples of breast tumours and metastases, with due care of the ethical aspects, as well as established breast cancer cell lines. MetaBre will also study genes and molecules that are already suspected of involvement in metastasis.This builds on previous work of the partners and will enhance understanding of the role of these molecules in metastasis, as well as identifying new therapies and diagnostic methods against these targets.
mechanisms of angiogenesis and invasion organ-cancer cell interactions development of new pharmacological therapies and diagnostic techniques preliminary clinical trials. MetaBre will use state-of-the-art Affymetrix chips for gene profiling and will develop novel in vitro and in vivo models for validation of molecular targets and screening of therapeutic molecules. Metastases will be detected in vivo with optical imaging of luciferaseexpressing cancer cells and magnetic resonance techniques.
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Progress
The MetaBre kick-off meeting (below) was successfully organised in February 2004 and received regional and national media coverage in Italy. As well as the MetaBre partners, the meeting was also attended by Dr Pavel Gromov of the Danish Cancer Society who will advise on the proteomics research. The research activities in the project include identification of new genes and proteins involved in molecular mechanisms of metastasis in breast cancer, as well as work on targets already identified. To assist the collaboration, inventories of cell lines and in vivo models available among the partners have been compiled. There was a strong emphasis in the first year of MetaBre on organising collection of tissue samples that will be used in gene profiling and proteomics work. Partner CRH is leader of this work package and they have supplied a number of tissue samples of liver and lung metastases, and primary breast tumours from their own collection. Several other partners have access to tissue banks and clinics and have also collected tissue samples. A meeting of the partners involved in gene profiling was arranged in Paris in April 2005, and a common specification sheet has been prepared.CRH collated the data on tissue samples into a confidential database. The gene profiling has mainly used the Affymetrix platform provided by partner PSK, but the partners will also use other microarray systems in order to maximise the opportunities for gene profiling in the project. The first gene profiling with Affymetrix has been completed on a breast cancer cell line sub-clone B02 developed by partner INSERM that strongly metastasises to bone. This has generated interesting results that are being analysed by all partners. Currently samples of clinical bone metastases are being collected in order to validate these data. Also analysis was successfully performed on liver and lung metastases and primary breast tumours, though good quality RNA was not extracted from all samples. Further analysis and comparison of gene profiles should identify genes of interest. Functional analysis will follow. Partner IRO has worked on identification of protein markers of organspecifity,particularly in lung and brain metastases.A number of proteins have been identified from analysis of organ-specific breast cancer cell lines, and these are being characterised and verified. For proteomic analysis,advanced methods are being implemented to obtain accurate results from smaller quantities of material. Partner WAU is investigating the role of carbohydrate antigens in breast cancer metastasis.So far no suitable cells lines have been found as models of the Sialyl LewisX antigen known to be found in 30-40% of breast cancers, so WAU aim to develop a modified cell line for this purpose. In comparison,TF-antigen is expressed in most cell lines and experiments are progressing with gene silencing using siRNAs. ULg is also using siRNAs to silence histone deacetylases, which are suspected to have a role in angiogenesis in breast cancer, for study with in vitro and in vivo models.
LUMC are working on some innovative tools for studying of gene expression in in vitro and in vivo models.They are also working towards a 3D model of epithelial-mesenchymal transition in breast cancer. Partner CMNS is studying the basic cell biology of MMP trafficking, and has also started work with UNIVAQ on the characterisation of the podosomes features of osteoclasts that are involved in the development of bone metastases through degradation of bone matrix. These may be similar or even identical to invadopodia of cells involved in degradation of extra-cellular matrix. ICR are working to understand molecular mechanisms of metastasis to lymph nodes and have been testing cell lines for expression of factors that are suspected of involvement. Work has started with a 3D epithelial cell culture and ICR will use microarrays to identify genes upregulated when cancer cells interact with the lymphatic endothelium. A number of new therapeutic approaches are being tested already in the project, against known molecular targets. UNIVAQ has built on previous work on the role of c-Src in the development of bone metastases. New results from in vivo experiments show that c-Src
Image of a bone metastasis obtained by 3 dimensional computerised micro-tomo-densitometry
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In MetaBre, metastases will be detected in-vivo with optical imaging of luciferase-expressing cancer cells and magnetic resonance techniques
Coordinator
Prof.Teti,Anna Department of Experimental Medicine University of LAquila Via Vetoio Coppito 2 67100 LAquila, Italy Phone: + 39 0862 433511 Fax: +39 0862 433523 E-mail: info@metabre.org Project web-site: www.metabre.org Key words: Breast cancer, metastasis, gene profiling, organ-specific
inhibitors have a significant effect on the incidence and growth of bone metastases. Also INSERM has found new evidence of interactions between breast cancer cells and blood platelets that stimulate bone resorption in osteolytic bone lesions. Image of a bone metastasis obtained by three-dimensional computerised micro-tomo-densitometry INSERM is testing endogenous anti-angiogenic agents such as thrombospondin.These have been transfected into the B02 cell line to assess their effect on the growth of bone metastases in-vivo. Also PSK are testing new compounds that inhibit an adhesion molecule, known to be important for the vicious circle between breast cancer cells and osteoclasts. In vivo bioluminescent imaging has been used to detect bone metastases at an early stage, thus permitting short-duration in vivo experiments. Many of the molecular targets of MetaBre will be suitable as prognostic markers.The University of Ghent has already identified the soluble extra-cellular fragment of N-cadherin as a marker of invasive breast cancer and is developing an ELISA assay for accurate and rapid detection. This has involved development of suitable monoclonal antibodies and recombinant sN-cadherin for calibration of the ELISA. Tests with serum samples from patients have commenced. The sN-cadherin marker is useful not only for following progress of breast cancer treatment but also for other diseases. IRO has also commenced work on magnetic resonance imaging and magnetic resonance spectroscopy for detection of brain metastases. This is useful for non-invasive measurement of experimental metastases in vivo and also may ultimately have a clinical application. The project has received good publicity through two press conferences in Italy and Belgium, and being profiled in Quest magazine in December 2004. A website has been developed as well as a project flyer. Some of the project partners attended the Metastasis Research Society meeting in September 2004 and a highprofile presentation is planned for a major European breast cancer conference in 2006.
Partners
Dr. Buccione, Roberto, Consorzio Mario Negri Sud (CMNS), Italy Dr. Lidereau, Rosette Centre Rn Huguenin (CRH), France Dr. Clezardin, Philippe INSERM U664, France Dr. Clement-Lacroix, Philippe, ProSkelia SaS (PSK), France Dr. van der Pluijm, Gabri, Leiden University Medical Centre (LUMC), The Netherlands Dr.Williger, Ben-Tsion CancerTek Pharmaceuticals Ltd (CTP), Israel Prof. Ugorski, Maciej,Wroclaw Agricultural University (WAU), Poland Dr. Eccles, Suzanne, Institute of Cancer Research (ICR), United Kingdom Dr. Sierra, Angels, Institut de Recerca Oncologica (IRO), Spain Prof. Bracke, Marc, Ghent University (UGent), Belgium Prof. Castronovo, Vincent, University of Lige (ULg), Belgium
Acronym: MetaBre Project number: LSHC-CT-2004-506049 EC contribution: 4 005 294 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/01/2004
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ENACT
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European Network for the identification and validation of antigens and biomarkers in cancer and their application in clinical cancer immunotherapy
Summary
Prospective clinical material will be collected during the life of the programme and new and existing tumour tissue, PBMC and serum banks will be available for use in the study.This common resource of material will be distributed to partners for the immunological,genomic, biochemical and proteomic analysis of tumour and host response(s) to immunotherapy.The results will be subjected to bioinformatic analysis in the context of clinical outcome of vaccine-based immunotherapy trials from five European clinical centres.Analysis of the results in the context of gender will allow prominent inter- and intra-tumour / host biomarkers to be identified for translation back into clinical practice.
Aim
ENACT aims to identify markers of response and tumour antigens that associate with ovarian, breast and prostate cancer and melanoma progression and resistance to immunotherapy. The present application will address these issues in a number of ways and directly analyse the important biomarkers that are expressed by cancer and may therefore be considered as novel targets by establishing a European network for collaboration.The cancer types to be included will address the issue of sex-related biomarkers associating with resistance to therapy. Cell biological, immunological, biochemical and molecular biology-based technologies will be used and knowledge generated in this project will not only result in a desired and highly competitive technological base for vaccine development (not necessarily restricted to cancer vaccines), but also will provide a better understanding of basic biological mechanisms underlying antigen presentation and recognition of tumours by CD8+ and CD4+ T lymphocytes and NK cells.
Problem
Cancer remains a major health problem, with untold physical, psychological and economic costs to society. Elimination of cancer would reduce health care costs and enhance quality of life. Along with cardiovascular disease and ageing, it is currently the most intractable source of suffering and health care cost. Recent results from immunotherapy trials would suggest that inducing tumourspecific T-cell responses to tumour antigens can, in some patients, cause the regression of tumours or the stabilisation of the disease. However the mechanisms underlying the failure of immunotherapy to control and destroy residual cancer remains to be fully established. Experimentally, it can be shown that tumour rejection is mediated by CD8+CTLs aided by CD4+T-helper cell activity. However animals that fail to respond may fail to demonstrate a pronounced (if any) CTL response. In addition data from many laboratories have shown that tumour escape from CTLs can occur as a result of downregulation of MHC class I antigens, and in some instances cancer cells that show successive mutations may demonstrate progressive and complete loss of MHC expression.The current status of our understanding of adoptive cancer immunity also suggests that immune tolerance can equate with lack of response, with possible regulation by CD4+CD25+T-lymphocytes as well as other regulatory cells. Breaking tolerance through immunotherapy therefore represents one possible approach to promote T-cell responses and tumour regression.
Expected results
1. to establish a database for the analysis of clinical and experimental results in order to identify markers related to the outcome of immunotherapy 2. to provide clinical material and cancer cell lines for scientific investigation conducted within the programme 3. to assess the cellular and humoral immune response in patients undergoing immunotherapy 4. to identify biomarkers using proteomics and computer based algorithms 5. assessment of the importance of immunological, genetic and proteomic biomarkers as indicators of therapeutic response related to gender 6. dissemination of the information to the scientific community and the community at large.
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The use of therapeutic cancer vaccines still has to be firmly established and previous clinical trials strongly indicate that not all patients benefit from receiving such treatment. The present study will allow us to establish whether the results of ENACT can be used in a clinical setting. The identification of indicators of patient response to immunotherapy would allow clinicians to target vaccination to those patients who are most likely to respond.The findings of the present study could result in assays that could be used to predict treatment outcome and / or monitor patients during the course of treatment. This would benefit the health care industry and patient care and the findings may be applicable to cancers other than those included in the research programme. The approach will allow us to gain further scientific understanding of the immune response to tumour antigens, which may influence the development of future generations of cancer vaccine.This research represents a valuable contribution to the welfare of patients who would be considered to be suitable candidates for vaccine-based therapy.
Coordinator
Prof. Rees, Robert Interdisciplinary Biomedical Research Centre Nottingham Trent University Faculty of Science and Land Based Studies School of Science Clifton Lane Nottingham, NG11 8NS, United Kingdom E-mail: robert.rees@ntu.ac.uk Project web-site: https://www.enactcancerresearch.org Key words: Tumour progression, biomarkers, tumour escape, melanoma, prostate cancer, ovarian cancer
Partners
Laboratory of Clinical Immunology, University Hospital, Sofia, Bulgaria Abt.Innere Medizin II Zentrum fur Medizinische Forschung, ZMF, Universitatsklinikum Tuebingen, Germany Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden INSERM U463, Institue de Biologie, Nantes, France Institute of Medical Biochemistry, Jagiellonian University Medical College, Krakow, Poland Biomedical Research Study Centre, University of Latvia, Riga, Latvia Departamento de Analisis Clinicos, Hospital Universitario, Granada, Spain Skin Cancer Unit (DO70), University Hospital Mannheim, Germany Department of Immunology, Institute for Cancer Research, Section for Immunotherapy,The Norwegian Radium Hospital, Oslo, Norway The Anthony Nolan Research Institute,The Royal Free Hospital, London, United Kingdom Loreus Ltd, Nottingham, United Kingdom Dept. of Immunology, Hellenic Anticancer Institute, Athens, Greece Onyvax Ltd, St Georges Hospital Medical School, London, United Kingdom
Acronym: ENACT Project number: LSHC-CT-2004-503306 EC contribution: 4 166 513 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/01/2005
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Prognosis and therapeutic targets in the Ewing family of tumours

Summary
The project through collaborative studies will define prognostic markers and new therapeutic targets in the Ewings sarcoma family of tumours (ESFT) to provide rigorous scientific justifications for the development of clinical trials for this rare disease, which is mainly manifested in children.The main objective of this project is to evaluate the prognostic relevance of selected markers (EWS/FLI-1, secondary genetic alterations, CD99, IGF-IR, NOVH, erbB-2 and TTF1) and the effectiveness of therapeutic approaches targeting some of these molecules. Another major goal of the project is the construction of ESFT c-DNA microarrays and tissue arrays, which will be used for the analysis of different histological subtypes of ESFT, primary and metastatic tumours and poor and good responders to chemotherapy. This will lead to: 1) the definition of forthcoming risk-adapted strategies and targeted molecular treatments to be advantageously combined with established therapies; 2) improved quality of life and survival for ESFT patients; 3) prevention on risk in groups at risk. a.The histogenesis of ESFT is still uncertain and the normal counterpart of ESFT cells is still unknown. b.The lack of prognostic factors obliges the use of non-differentiated treatments for all patients, leading to over-treatment of those patients who could benefit from less toxic therapies.The reduction of delayed side-effects is particularly important in this disease considering the young age of the patient and their long life expectancy. c. In the current state of ESFT treatment there is a survival plateau (around 60% for patients with localised disease and 25% for highrisk groups) due to the lack of new drugs and toxicity that impedes more intense use of existing drugs. The identification of new targets for innovative therapeutic strategies is, therefore, strongly needed for this tumour. Progress is generally hampered by the rarity of the disease (in Europe about 400 cases/year) implying a limited number of cases for effective research. Moreover, because ESFT is an orphan disease, no private company will develop new therapeutic tools and take on the costs to conduct pre-clinical investigation.
Aim
The project will define prognostic markers and new therapeutic targets in the Ewings sarcoma family of tumours (ESFT) through collaborative studies to provide rigorous scientific justification for the development of new therapeutic strategies for this rare disease, which is manifested for the most part in children. Goals expected to be achieved: 1.With respect to the problem of toxicity, the project, by identifying the clinical relevance of a number of markers, may allow the differentiation of patients in terms of risk to recur.This will enable more aggressive treatments where these are justified, and avoid toxicity in cases where such treatments may be known to be unnecessary, with particularly significant consequences for the quality of life of the patients. 2. Successful treatment of therapy-resistant patients requires new strategies. Indeed, there is a desperate need for new therapeutic approaches in ESFT. A thorough study of the pre-clinical effectiveness of new targeted therapeutic strategies will be performed with the aim of the identification of the Achilles heel in this disease and the consequent development of a tailored biological therapy to be used in association with conventional chemotherapy. 3. By providing an organisational framework for collaboration the project will also allow multi-centre collection and analysis of cases as well as suitable collaborative research to allow genetic studies for the screening of high-risk patients and patients responding differently to chemotherapy.
Problem
The Ewings sarcoma family of tumours (ESFT) includes: Ewings sarcoma; primitive neuroectodermal tumour; Askins tumour; paravertrebral small-cell tumour; atypical Ewings sarcoma. ESFT represents a peculiar entity in oncology. In spite of its absolute rarity (about 300-400 cases per year in Europe), ESFT is one of the most frequent solid neoplasm in paediatric age groups. Due to this fact, its impact on the health system is particularly important.The adoption of multimodal treatments with very aggressive chemotherapeutic regimens have significantly improved the chance of survival of ESFT non-metastatic patients, shifting the five-year survival rates to around 60%.Despite these important clinical results,which are usually difficult to obtain in rare diseases, several problems related to histogenesis, prognosis and treatment response are still open. In particular:
Histological features of Ewings sarcoma
Ewings sarcoma: stain for CD99
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Expected results
1.The identification of prognostic factors in ESFT as a basis for the definition of individual therapeutic regimens, which would limit the incidence of acute side-effects and long-term morbidity as well as the economic and social consequences of intensive chemotherapy. 2.The definition of patient selection criteria to be used as a basis for beginning a pivotal clinical trial. 3.The creation of new therapeutic bullets against ESFT.They will be available at the end of the project as new drugs for ESFT treatment, together with the required toxicological and pharmaco-kinetics studies.This is an important point because ESFT is an orphan disease and no private company will develop new therapeutic tools and take on the costs of conducting pre-clinical investigation. 4. New therapeutic strategies for oncologists to increase the survival rate of ESFT patients through the pre-clinical evaluation of new drugs and strategies based on an immunological approach. 5. New clues in the diagnosis and the screening of high-risk groups through the creation of an extensive tissue bank and the genetic profile analysis (cDNA microarray and tissue array analyses) of these samples.
on the biomedical world. Specified actions of the project are devoted to dissemination activities to ameliorate harmonious relations between cancer researchers and society, with particular regard to patient associations.
Coordinator
Dr Picci, Piero Department of Musculoskeletal Oncology I. F. Goidanich Istituti Ortopedici Rizzoli Via di Barbiano 1/10 40136 Bologna, Italy Phone: + 39 051 6366759 Fax: + 39 051 582244 E-mail: piero.picci@ior.it Project web-site: under construction (www.prothets.org). There will be a link in: http://www.ior.it. Key words: Ewings sarcoma, EWS/FLI1, CD99, insulinlike growth factor, microarrays
Therefore the project,aiming to ameliorate treatment of ESFT,will have an impact on child health.In particular,the main objective of this project is to develop patient-oriented strategies for Ewings sarcoma patients by: a) integrating different disciplines and advanced technologies to develop effective approaches or new tools for diagnosis, prognosis and treatment. b) elucidating the contribution of specific molecular and genetic factors to the histogenesis of the disease. This work will unlock the potential of the individual studies carried out by each of the consortium partners, and it will define targeted therapeutic strategies of practical value in clinical settings and the clinical relevance of a number of markers that will allow the differentiation of patients in terms of risk of recurrence. It will also unlock the biological and clinical information potential behind multi-centre data collection and genetic analysis of patients, bringing basic knowledge to the application stage. Progress is generally hampered by the rarity of the disease, implying a limited number of cases for effective research.The creation of a multi-centre tissue bank and data collection will help to overcome a big obstacle.The application of new technology will be used to identify ESFT-related molecular mechanisms. The gene expression profile of ESFT will be analysed and new markers to be used for diagnostic, prognostic and therapeutic purposes will be identified. The project made efforts in the integration of multi-disciplinary research capacities across Europe. The consortium includes pathologists, oncologists, immunologists, and molecular and cellular biologists. Moreover, PROTHETS lays emphasis on collaboration with small and medium-sized enterprises (SMEs),devoted to the development of specific tools for prognostic and therapeutic applications. Finally, the development of evidence-based guidelines will ensure that the knowledge held and developed by and within the project will be distributed as widely as possible to have the highest possible impact
Partners
Laboratory of Oncologic Research, Istituti Ortopedici Rizzoli, Bologna, Italy Institut National de la Sant et de la Recherche Mdicale, Nice, France Laboratory for Experimental Orthopaedic Research, University Hospital of Mnster, Germany Haartman Institute, Department of Medical Genetics, University of Helsinki, Finland Department of Pathology, Medical School, Hospital Clinico Universitario,Valencia, Spain Laboratory for Molecular Biology, Childrens Cancer Research Institute, St. Anna Childrens Hospital,Vienna, Austria Universit Paris 7 Denis-Diderot, Paris, France Centre National de la Recherche Scientifique, UMR8121 CNRS Institute Gustave Roussy PR2,VilleJuif, France Belozersky Institute of Physico-Chemical Biology, Moscow State University, Russia GenX Laboratories srl,Vignate, Italy Mabgne S.A., Ales, France
Acronym: PROTHETS Project number: LSHC-CT-2004-503036 EC contribution: 2 530 500 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/01/2005
220
P-MARK
CANCER
Validation of recently developed diagnostic and prognostic markers and identification of novel markers for prostate cancer using European databases
Summary
The current diagnostic markers for prostate cancer have a low specificity and lead to over-diagnosis and over-treatment due to the detection of small non-aggressive or non life-threatening cancers. In addition, there are currently no efficient serum or urine markers available for the prognosis of this malignancy.The P-Mark project will address the growing need for improved diagnostic and prognostic markers for prostate cancer. promising markers. Novel serum and urine markers will be identified in clinically well-defined biomaterials using innovative mass spectrometry tools, and antibody-based immunoassays will be developed for these markers.The novel markers will be evaluated for their clinical importance using these assays. Recently developed promising markers that prove their clinical value during the evaluation will be validated on a sample set derived from two European screening studies (the ERSPC study and the ProtecT study). Eventually, the markers arising from this project will be offered to SMEs for commercialisation and to ongoing large European clinical studies for clinical implementation.
Problem
In Europe, prostate cancer (Pca) is the second most frequent lethal malignancy in men. Yearly about 40 000 men die of Pca in the EU countries.There is a slow increase of mortality and in addition, due to an ageing population, a 50% increase in incidence is expected by 2020. So far,the only chance for cure is early detection and treatment by either surgery or radiotherapy.Diagnosis of Pca is made by ultrasound guided transrectal biopsy of the prostate for histology. An increased level of the serum marker prostate specific antigen (PSA) predominantly indicates such a biopsy.A major disadvantage of this diagnostic marker is its low specificity, resulting in a significant amount of false biopsy indications.PSA is a normal excretion product of the prostate cells and is therefore not only found in the circulation of men with prostate cancer but also of men with a normal prostate and men with benign prostatic hyperplasia, a phenomenon that is associated with ageing. Nevertheless,PSA is the standard marker for Pca diagnosis and has been demonstrated to be effective in advancing the diagnosis by detecting Pca at earlier stages.A growing number of men choose to be screened for Pca by PSA analysis,even up to 60-70% of men in the USA.However, the value of screening for Pca has not been established yet and is currently the subject of investigation in the European Randomised Study of Screening for Prostate Cancer (ERSPC). A major drawback of the standard diagnostic tools for Pca is the detection of small non-aggressive or non life-threatening cancers, leading to over-diagnosis and overtreatment, as well as the detection of tumours that are too advanced to cure. Currently, there are no serum or urine markers available for the prognosis of Pca at early disease stages apart from PSA.It is apparent that improved diagnostic and prognostic serum or urine markers are required that can discriminate men with clinically irrelevant Pca,curable Pca, or life-threatening Pca.
Expected results
1. the establishment of a serum biorepository and a urine biorepository for the discovery, evaluation and validation of diagnostic and prognostic Pca markers 2. the discovery of novel Pca markers in human body fluids by innovative mass spectrometry tools 3. the establishment of the clinical utility of recently developed promising Pca markers, including PCA3DD3, bone morphogenetic protein-6 (BMP-6), osteoprotegerin (OPG), nicked PSA, human kallikrein 2 (hK2) and cytochrome P450 3A5*3 polymorphism (CYP3A5*3) 4. the validation of Pca markers and identification of risk groups in the general population in Europe 5. the development of guidelines for cost-efficient strategies for Pca detection and therapy.
Aim
For three years, P-Mark will search for improved diagnostic and prognostic Pca markers by the identification and evaluation of novel markers as well as the evaluation and validation of recently developed
221
CANCER
P-Mark will evaluate the clinical value of recently developed promising Pca markers and of novel Pca markers. If a marker meets the defined P-Mark marker criteria (improved sensitivity and specificity over current markers for diagnosis or prognosis; indicative for early detection, over-treatment, risk for progression or therapy resistance; clinically relevant target in relation to tumour biology; reliable and cost-efficiently determinable in non-invasively obtained specimens; stable component in specimen), it will be developed further for the validation in a mono-centre or multi-centre setting. In addition, the marker will be offered to commercial enterprises for commercialisation.Validation will lead to guidelines for cost-efficient strategies for detection and treatment as well as recommendations for marker application, that have to be discussed in the public domain of related European professional societies.Validated markers will be offered to the principal investigators of ongoing screening studies in Europe for implementation in the study.Taken the duration of P-Mark into consideration (three years), clinical marker implementation will continue beyond this project.
Coordinator
Prof. Bangma, Chris H Department of Urology Erasmus MC, room H1074 Dr. Molewaterplein 40, 3015 PO Box 2040, 3000 CA Rotterdam,The Netherlands Phone: + 31 10 463 3607 Fax: + 31 10 463 5838 E-mail: h.j.vanalphen@erasmusmc.nl Project web-site: http://www.p-mark.org Key words: prostate cancer, markers, diagnosis, prognosis, serum, urine, proteomics, mass spectrometry
Partners
Department of Laboratory Medicine, Division of Clinical Chemistry,Wallenberg Laboratory, University Hospital Malm, Sweden Department of Urology, University Hospital Malm, Sweden Department of Experimental Urology, University of Nijmegen,The Netherlands Department of Urology, University of Sheffield, United Kingdom Department of Clinical Chemistry, Helsinki University, Central Hospital, Finland Department of Biotechnology, University of Turku, Finland Centre for Pharmacy, Analysis of Biomacromolecules, University of Groningen,The Netherlands Innotrac Diagnostics OY,Turku, Finland CanAg Diagnostics AB, Gteborg, Sweden
Acronym: P-Mark Project number: LSHC-CT-2004-503011 EC contribution: 3 480 764 Instrument: Specific Targeted Research Project Duration: 36 months Starting date: 01/11/2004
222
EUSTIR
CANCER
A European strategy for the integration of research on breast cancer

Summary
The overall objective is to create a permanent European overview process for the award, audit and recording of all research on breast cancer: This will be the creation of the funding bodies themselves which, for each project, will retain the absolute power of award. The project aims to create: 1.A European overview process for project proposals received by all funding bodies.This will i) prevent research from being funded for similar work in multiple projects ii) result in a few large, rather than multiple small series, which are much more likely to yield definite results. 2.A body of the leading researchers in breast cancer which agree the areas most likely to give results of clinical relevance and agree certain issues that must be included in all proposals (such as validation of the results). 3.An audit process of research work.This addresses the problem that many projects do not address their aims.The audit outcomes will be accessible to research funders, so that institutes most likely to complete valuable projects are identified (and the converse!).This project will be divided into 3 parts; i) a workshop of leading European research workers in breast cancer to define the most important areas for research and to make suggestions on an overview process ii) a workshop of the funding organisations & other interested parties to discuss and agree a strategy for harmonising research in the identified areas and iii) validation of projects funded to date against criteria established within the project.
Problem
The present methods of awarding research grants in cancer suffer from many defects and appear to result in repetitive research, often with no clear result and no clinical relevance.There is no agreement as to which areas are the most important, there is no attempt to ensure claims are validated,there is no audit process for success/failure and no ranking of ability of individual units to complete projects and their value.This means that monies for research are often spent poorly.
Aim
1. LONG TERM AIMS To harmonise breast cancer research through individual funding organisations operating within Europe To encourage research to be focused on that which will have ultimate clinical application To ensure that validation is a part of the design of all applications To establish an audit system backed by a database that allows assessment of the success rate of individual research groups. 2. PROJECT SPECIFIC AIMS To bring together all organisations involved in developing,supporting and undertaking breast cancer research in Europe to design a strategy for the pan-European harmonisation of breast cancer research. To develop a process of audit of completed research whereby research projects will also be judged as to whether they have advanced the science and to what degree they are relevant to clinical practice. To maintain a database of projects and of the audit of completed projects Audit of past projects and production of a policy paper for implementation To influence journal editors, to ensure higher standards are set for acceptances for publication of results; validation and clinical relevance will be the most important issues.
223
CANCER
Expected results
A European overview process for project proposals received by all funding bodies.This will i) prevent research from being funded for similar work in multiple projects ii) result in a few large, rather than multiple small data sets, which are much more likely to yield definitive results 2.Agreement and ranking of the areas most likely to give results of clinical relevance. 3.Agreement on certain issues that must be included in all proposals (such as validation of the results) 4.An audit process of the results of funded research.This will initially show if the contentions expressed above with regard to funded research, are in fact correct.The audit outcomes will be accessible to research funders, in that institutes most likely to complete valuable projects will be identified (and the converse!).
Coordinator
Prof. Roger Blamey Breast Institute Nottingham City Hospital NHS Trust Hucknall Road Nottingham NG5 1PB, United Kingdom Tel: +44 115 962 5707 Fax: +44 115 962 7765 Email: wbartlanm@ncht.trent.nhs.uk Key words: breast cancer, funding, harmonisation
Aside from the obvious and intended application in breast cancer funding across Europe,the model created by the project can be applied to many funding areas where multiple sources of funding create the same problems as seen in breast cancer.
Acronym: EUSTIR Project number: LSSC-CT-2005-517659 EC contribution: 198 640 Instrument: Specific Support Action Duration: 24 months Starting date: 01/01/2006
224
EUROCAN +PLUS
CANCER
Feasibility Study for Coordination of National Cancer Research Activities

Summary
A key issue remains how effective coordination of Cancer Research in Europe can see the European Union (EU) benefit from the advantage of scale, which its population provides. Cancer research in EU is fragmented and frequently duplicative. Resources are wasted and implementation of closer cooperation to develop a strategy for Cancer Research by the Member States would clearly be cost-efficient and hasten the development of major advances and their delivery to the population. Barriers to collaboration in cancer research need to be identified and ways sought to encourage the development of collaborations in the Member States. A further obstacle is the lack of common core elements in the curriculum of professionals.Common quality standards in training are needed to facilitate the collaboration at European level as well as the mutual recognition of the qualifications between European countries and therefore the mobility of researchers and physicians.The situation is particularly exemplified by the absence of recognition of Oncology as a Medical discipline by many European countries and its variable status in most Member States. Consequently, although a large amount of financial resources is involved, and a substantial portfolio of initiatives is carried out, cancer research efforts are not currently benefiting from the advantages that a coherent and more co-ordinated framework would bring about.
Aim
On the basis of an overview as complete as possible of Cancer research in Europe, objectives of the project are to: 1. Identify the fields, topics and research subjects where the lack of co-ordination of national activities is particularly detrimental for the progress of knowledge and the quality of care; 2. Identify those specific fields,topics and research subjects where the awareness of the need, as well as the willingness and readiness to achieve a better co-ordination, are established enough as to make such an achievement likely; 3. Explore the suitability, for this purpose, of the various support schemes available in the 6th Framework Programme (Co-ordination actions; ERA-NET schemes;Article 169); 4. Explore,in particular,the interest and feasibility of an initiative based on article 169 (participation of the EU into national research programmes jointly implemented); 5. Help determine the means by which further exploring the possibilities and ways to progress in the direction of a better coordination (study, workshop, conference, survey); 6. Give orientation on all the issues above raised and practical recommendations on the last points.
Problem
Cancer remains a major Public Health problem worldwide with Europe hit hard and the situation set to worsen in absolute terms as the population ages.Around one half of cancer patients still die from their disease. On the other hand, there are currently great expectations that we are on the brink of making huge progress against the disease. Elucidation of the human genome and rapid advances in understanding details of its function allied to rapid progress in technology,gives great hope of rapid advances taking place.The current era offers more real hope than any previous. Cancer remains the subject of significant research effort at both the European level and in the Member States. Between 2002 and 2006, the European Union will be devoting more than 435 Million to this field of research.This is in addition to national funding in Member States. An important aim for the Commission is to achieve a better framework for collaboration in cancer research in Europe, and there is a recognition that coordination of national cancer research efforts at the European level is far from being achieved. Among the key elements proposed to explain this situation are the barriers between disciplines and fields of research; the fragmentation of research activities dedicated to the different types of cancer and the resultant sub-optimal critical mass; the weakness of the links between basic, applied and clinical research, leading to a rather limited integration of basic and clinical research;and the implementation of all these activities mainly in a national framework and a national context. As a consequence, Europe is unable to fully benefit from the advantage of scale afforded by its 500 million population. Europe is at present, and has been for many years, unable to retain many of its most talented scientists and is unable to provide a scientific environment capable of attracting top young scientists from outwith the continent. In addition, there is no national incentive to promote mobility within the Member States. Consequently, the development of transnational research activities is impeded by the obstacles to the mobility of researchers.
Expected results
The project shall provide key answers to the following questions through the exploration of barriers to Research Collaboration in the EU in specific fields as well as by dealing with some of the key issues including mobility of cancer research workers throughout the European Union: Irrespective of the prospects generated by considerations of alternative legal, governance and financial matters, including article 169, what can be done to facilitate Cancer Research in the European Research Area? What could be done to enhance Cancer Research in the European Research Area by new application(s) of available legal, governance and financial considerations, including Article 169?
225
CANCER
The project is certainly going to have a major impact on the structuration of Cancer Research,basic and clinical,throughout the EU.Furthermore, the EU will dispose of concrete and practical recommendations for the definition of priorities in research programmes.
University College Dublin Dublin, Ireland Dr Jan-Willem Hartgerink International Affairs Department Ministerie van Volksgezondheild,Welzijn en Sport The Hague,The Netherlands Prof. David Kerr Department of Clinical Pharmacology The Chancellor, Masters and Scholars of the University of Oxford Radcliffe Infirmary Oxford, United Kingdom Dr Peter Lange Unterabteilung 61: Gesundheit, Biowissenschaften Bundesministerium fr Bildung und Forschung Berlin, Germany Prof Jose Martin Martin-Moreno Professor of Medicine and Public Health Medical School, University of Valencia Valencia, Spain Prof Herbert Michael Pinedo VUmc Cancer Center Amsterdam Amsterdam,The Netherlands Ulrik Ringborg, MD, Ph.D. Radiumhemmet-Dept. of Oncology Karolinska University Hospital Solna Stockholm, Sweden Prof. Dimitrios Trichopoulos Department of Hygiene and Epidemiology School of Medicine National and Kapodistrian University of Athens Athens, Greece Prof Thomas Tursz Direction Gnrale Institut Gustave Roussy Villejuif, France
Coordinator
Dr Peter Boyle International Agency for Research on Cancer 150 cours Albert Thomas 69008 LYON Tel.: +33 4 72 73 85 77 Fax: +33 4 72 73 85 64 E-mail: director@iarc.fr
Partners
Prof. Harry Bartelink The Netherlands Cancer Institute Department of Radiotherapy The Netherlands Cancer Institute/ Antoni van Leeuwenhoek ziekenhuis Amsterdam,The Netherlands Dr Filippo Belardelli Department of Cell Biology and Neurosciences Istituto Superiore di Sanita' Rome, Italy Prof. Julio Celis Institute of Cancer Biology Danish Cancer Society Copenhagen, Denmark Dr Diana Dunstan MRC Research Management UK Medical Research Council London, United Kingdom Prof. Alexander M.M. Eggermont, MD, PhD Surgical Oncologist Erasmus University Medical Center Department of Surgical Oncology Erasmusc MC - Daniel Den Hoed Cancer Center Rotterdam,The Netherlands Prof. John M Fitzpatrick Surgical Unit- Mater Misericordiae Hospital
Acronym: EUROCAN+PLUS Project number: LSSC-CT-2005-015197 EC contribution: 3 000 000 Instrument: Specific Support Action Duration: 24 months Starting date: 2005
226
Indexes
Acronym Contract number Coordinator 228 230 232
Index by acronym
ActinoGEN Active p53 AGEACTION AMIS ANABONOS Angiotargeting APOPIS AUTISM MOLGEN AUTOROME BIOCARE Bloodomics BrainNetEurope II BRECOSM CANCERDEGRADOME CCPRB Cells into Organs COBRA Diabesity DNA METHYLATION ECRIN-RKP Eicosanox EMBIC1 EMIL1 ENACT ESNI course 2003
70 170 156 77 152 166 93 106 62 164 18 102 212 182 196 148 82 32 206 14 12 46 73 217 135
eTUMOUR EUGENE EUGINDAT Eumitocombat EURAPS EUR-INTAFAR EUROCAN + PLUS EuroClot Euroglycanet EUROHEAD EUROMEMO European LeukaemiaNet European MCL Network EUROSCA EuroWilson EUROXY EUSTIR EVGN EXGENESIS FENS Forum 2004 FIRST GEHA GENADDICT GENESKIN GRIPANNT
198 236 58 44 60 68 225 26 47 111 132 202 209 97 52 194 223 20 34 137 179 144 95 49 124
228
IMMIDIAB INTACT INTERDEVO LINK-AGE MAESTRO MetaBre micro-MATRIX MIMAGE MOL CANCER MED MOLSTROKE Mutp53 Myocardial Repair NCL-MODELS NeuroDisseminator NEUROKCNQPATHIES NeuroNE NEWMOOD Orphanplatform OSTEOGENE PainGenes P-MARK PNEUMOPEP PREVIS PRIMA PROMEMORIA
141 162 129 150 195 214 85 142 191 24 187 28 116 131 118 100 90 64 154 122 221 75 79 168 88
PROTHETS PWS RABRE SPASTICMODELS STRESSPROTECT STROMA SYNSCAFF TONECA TRANSBIG TRANSFOG VIRGIL X-ALD
219 56 139 113 126 185 108 39 200 176 73 120
229
Index by contract number
LSHC-CT-2003-502932 LSHC-CT-2003-503233 LSHC-CT-2003-503297 LSHC-CT-2003-504586 LSHC-CT-2003-506803 LSHC-CT-2004-502943 LSHC-CT-2004-502983 LSHC-CT-2004-503011 LSHC-CT-2004-503036 LSHC-CT-2004-503094 LSHC-CT-2004-503216 LSHC-CT-2004-503224 LSHC-CT-2004-503306 LSHC-CT-2004-503351 LSHC-CT-2004-503426 LSHC-CT-2004-503436 LSHC-CT-2004-503438 LSHC-CT-2004-503465 LSHC-CT-2004-503564 LSHC-CT-2004-503569 LSHC-CT-2004-503576 LSHC-CT-2004-504587 LSHC-CT-2004-504743 LSHC-CT-2004-505785 LSHC-CT-2004-506049
194 185 182 206 162 191 187 221 219 198 202 212 217 209 200 179 176 196 195 173 170 168 166 164 214
LSHM-CT-2003-502852 LSHM-CT-2003-502941 LSHM-CT-2003-503020 LSHM-CT-2003-503041 LSHM-CT-2003-503051 LSHM-CT-2003-503254 LSHM-CT-2003-503304 LSHM-CT-2003-503330 LSHM-CT-2003-503335 LSHM-CT-2003-503382 LSHM-CT-2003-503413 LSHM-CT-2003-504468 LSHM-CT-2004-005033 LSHM-CT-2004-005139 LSHM-CT-2004-005166 LSHM-CT-2004-005206 LSHM-CT-2004-005224 LSHM-CT-2004-005264 LSHM-CT-2004-005268 LSHM-CT-2004-005272 LSHM-CT-2004-005310 LSHM-CT-2004-502800 LSHM-CT-2004-502987 LSHM-CT-2004-503038 LSHM-CT-2004-503039
58 154 152 32 116 20 97 93 82 113 79 148 12 129 95 24 70 62 26 34 126 122 120 118 102
230
LSHM-CT-2004-503116 LSHM-CT-2004-503245 LSHM-CT-2004-503270 LSHM-CT-2004-503359 LSHM-CT-2004-503430 LSHM-CT-2004-503474 LSHM-CT-2004-503485 LSHM-CT-2004-504837 LSHM-CT-2004-504839 LSHM-CT-2004-511963 LSHM-CT-2004-511995 LSHM-CT-2004-512013 LSHM-CT-2004-512020 LSHM-CT-2004-512039 LSHM-CT-2004-512040 LSHM-CT-2004-512093 LSHM-CT-2004-512138 LSHM-CT-2004-512158 LSHM-CT-2005-005223 LSHM-CT-2005-005320 LSHM-CT-2005-512012 LSHM-CT-2005-512053 LSHM-CT-2005-512099 LSHM-CT-2005-512117 LSHM-CT-2005-512131
44 39 144 73 52 90 18 111 41 14 108 36 142 100 146 77 68 106 60 124 88 156 75 49 47
LSHM-CT-2005-512136 LSHM-CT-2005-513866 LSSC-CT-2005-015197 LSSC-CT-2005-517659 LSSM-CT-2003-502801 LSSM-CT-2003-502993 LSSM-CT-2003-503373 LSSM-CT-2003-504752 LSSM-CT-2004-005100 LSSM-CT-2004-503246 LSSM-CT-2004-511992 LSSM-CT-2005-013043
56 150 225 223 85 135 132 131 137 64 28 139
231
Index by project coordinator
Adlkofer, Franz Andrew, Peter W. Aym, Sgolne Bailey,Anthony James Bangma, Chris H. Berger, Johannes Bjerkvig, Rolf Blamey, Roger Blandino, Giovanni Bock, Elisabeth Boyle, Peter Brahme,Anders Brambilla, Riccardo Casari, Georgio Castro-Lopes, Jos Celda, Bernardo Chaouat, Grard Claussen, Bjrgulf Coppes, Rob De Libero, Gennaro Deakin, Bill Demotes-Mainard, Jacques Devor, Marshall Di Luca, Monica Dickson, Suzanne L.
93 75 64 106 221 120 166 223 170 88 225 164 132 113 137 198 146 41 179 24 90 14 122 108 32
Dillner, Joakim Dreyling, Martin Durston,Anthony J. Dyson, Paul Ebbesen, Peter Edwards, Dylan Fawcett, James Ferrari, Michel Foekens, John A. Franceschi, Claudio Frre, Jean-Marie Gautvik, Kaare M. Giavazzi, Raffaella Gilhus, Nils Erik Gutmann, Laurent Haeggstrm, Jesper Z. Hardie, D. Grahame Hehlmann, Rdiger Helin, Kristian Henriques Normark, Birgitta Herdegen,Thomas Holland,Tony Jalanko,Anu Kmpe, Olle Kirkwood,Thomas B.L.
196 209 148 70 194 182 100 111 206 144 68 154 185 135 82 12 34 202 162 79 126 56 116 60 156
232
Kitchen, Ian Kretzschmar, Hans Lenzen, Sigurd Marn, Oscar Matthijs, Gert Newbold, Robert Nicola, Jean-Philippe Olesen, Jes Osiewacz, Heinz D. Ouwehand,Willem H. Palacn, Manuel Petter Ottersen, Ole Piccart, Martine Picci, Piero Rees, Robert Resink,Thrse Rie, Olaf Roland, Per Schalken, J.A. Siminiak,Tomasz Sleeman, Jonathan Smeitink, Jan Smith, Ulf Spector,Tim Storme, Guy
95 102 39 129 47 191 195 139 142 18 58 124 200 219 217 24 97 131 168 28 212 44 36 26 176
Stuart, H. Ralston Tanner, Stuart Tavitian, Bertrand Tedgui,Alain Teti,Anna Thiesen, Hans-Jrgen Toussaint, Olivier van Strijp, Jos Vicente, Miguel Villarroel,Alvaro Wiman, Klas Zambruno, Giovanna Zoulim, Fabien
152 52 173 20 214 62 150 77 85 118 187 49 73
233
European Commission Major Diseases Research - Catalogue of Research Projects (2003-2005) in the Sixth Framework Programme Luxembourg: Office for Official Publications of the European Communities 2005 233 pp. 21.0 x 29.7 cm ISBN 92-894-8153-6
ISBN 92-894-8153-6
KI-61-04-880-EN-C
9 7892 89 481 5 33

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PROJECT SYNOPSES

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Major Diseases Research

Edited by Alain Vanvossel

Printed in Italy PRINTED ON WHITE CHLORINE-FREE PAPER

Foreword Introduction Overarching projects

Major Diseases Research (2003-2005)

Anti-Microbial Drug Resistance

Brain, neurological and psychiatric diseases

Human development and ageing

Major Diseases Research (2003-2005)

LINK-AGE ANABONOS OSTEOGENE AGEACTION

150 152 154 156

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

The clinical challenge

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

European Vascular Genomics Network

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Molecular basis of vascular events leading to thrombotic stroke

Major Diseases Research (2003-2005)

Work flow in the MOLSTROKE project

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Novel molecular targets for obesity and type 2 diabetes

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Metabolic studies during exercise in female and male volunteers

Major Diseases Research (2003-2005)

European network on functional genomics of Type 2 Diabetes

The Joint Programme of Activities of EUGENE 2

Major Diseases Research (2003-2005)

Graphical presentation of the research components of EUGENE 2 and their relationships

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Rational treatment strategies combating mitochondrial oxidative phosphorylation disorders

Model of human complex I, with the various subunits

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Schematic representation of the GENESKIN project

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)