Call Identifier: EOI.FP6.2002
Investigation the genetic origin of IBD in an Expert Network
q NEED & RELEVANCE: How the proposed research activities contribute to realising the objectives of a priority thematic area and why it requires a European mobilisation of activities and resources through the means of a Network of Excellence?
1.1 Aims and background
The proposed research activities of IBDEXPERTNET project fit into the priority research area 1.1.1.ii.a: Application-oriented genomic approaches to medical knowledge and technologies - Combating cardiovascular disease, diabetes and rare diseases. The other Sub-Thematic Priority is 1.1.2.i. Applied IST research addressing major societal and economic challenges. In the creation of the European Research Area, the implementation of shared cross boarder medical records for research and integration with bio-informatics (DNA-microarrays and automated & customized microarray interpretation) will create a new way of working to discover new IBD specific genes and proteomics for the benefit of the patient.
Both ulcerative colitis and Crohn disease appear to be more common in some industrialized countries such as Scandinavia, United Kingdom, North America and less common in Central and Southern Europe, Asia and Africa. Given data showing an increased incidence of ulcerative colitis in the United Kingdom, it is crucial that more studies be conducted in developing countries. While the incidence of Crohn disease has increased strikingly in many areas, the incidence of ulcerative colitis has remained fairly stable in most. This could be due to the rising number of community-based studies, as well as the improved accuracy in diagnosing Crohn’s disease. Although, the incidence of IBD among Blacks in Africa is low, infection rates are high, life expectancy is lower than in developed countries. Data from the USA suggest that rates are similar in Afro-American and Caucasian populations. Rates for Jewish populations may be slightly higher than in non-Jewish populations but this also varies geographically.
Recent epidemiological studies suggest that mortality rates for IBD are similar to that of the general population for the majority of patients. However, older patients with IBD and newly diagnosed cases with severe diseases are at increased risk of dying. There appear to be similar increased risks for developing colon carcinoma and hepatobiliary carcinoma among patients with Crohn disease and UC. There is an increased risk of developing rectal carcinoma in UC patients, an increased risk of developing carcinoma of the small bowel in Crohn disease patients, and an increased risk of developing lymphoma among males with Crohn disease.
1.2 Expected outcomes
Genetic factors play an important role in the pathogenesis of IBD, including ulcerative colitis (UC) and Crohn’s disease (CD). Evidence for genetic heterogeneity in IBD comes in part from the varying results of genetic linkage mapping studies. These studies are considered a model for the search of genes in multifactorial diseases. In the last decade several studies published about genetic heterogeneity in different ethnic groups. The search for specific IBD susceptibility genes has been difficult due to complex genetic factors, such as the absence of simple Mendelian inheritance patterns, incomplete penetrance, genetic heterogeneity, and the inclement of more than one susceptibility of the involved genes. The other perplex condition is the interaction among the immune system as the mediator of pathogenic mechanism, and the intestinal flora as the contributor of the crucial immune stimulus. Based on genetic details of different ethnic groups in different countries it could be great benefit to access that genetic knowledge and the related immune reactions via a Network of Excellence and share the developed diagnostic methods (DNA sequencing, microarrays, proteomic biochips) among the partners.
1.3 The added value of Europe
All the above listed factors are indicating a careful attention to genetic, environmental, and socio-economic factors must be accounted for studies we are willing to perform in IBDEXPERTNET. It is necessary to implement international collaborative studies using information technology tools (eForms and web electronic patient records in the format of Hyper Text Markup Language HTML/ Extensible Mark-up Language XML) to answer research questions addressing risk factors and disease natural history.
As the result of the project partners will able to compare the results of different factors in sera with genetic background, determine the factors are responsible for the disease and make recommendation for the best therapeutic modality.
q EXCELLENCE: The feasibility of putting together the critical mass of resources and expertise needed to achieve the network's objectives and to be a world force on the research activities proposed
2.1 Project Management
The co-ordinator of the project is Sandor G. Vari, MD Managing Director of VAREIMED Ltd., Hungary has extensive experience in the co-ordination of large scale EU projects. At the same time he is familiar with the USA system, since he was able to complete 11 Small Business Innovation Research Grants for the National Institute of Health and for the Department of Defence. He is capable to create platform for
Integration of activities:
o coordinated programming of the partners’ activities
o sharing of research platforms/tools/facilities
o staff mobility and exchanges
o relocation of staff, teams and equipment
o reinforced electronic communication networks
Activities to spread excellence
o training of researchers and other key staff
o dissemination and communication
o networking activities to assist knowledge transfer
all within a unified management structure.
The subcontractor of VARIMED Ltd. is VITAMIB SARL. France will provide the IT support for the eForms, and INFONET from Slovenia the web based shared medical record and for the project management using web management tool: Project NetBoard.
2.2 Joint Research Activities
Scientific co-ordinator: Professor A. Salvador Peña Very extensive studies on associations of different genetic factors and IBD, including genetic typing for IL-1B, TGFB, IL-1RA, HLA, TNFA, LTA, FAS, NOD2/CARD15. Has existing collaborations with the Hungarian group. International director of IBD Unit, Department of Gastroenterology, Hospital Clínico San Carlos, Madrid, Spain. He is capable to create platform for
Joint research activities
o a programme of joint research, possibly long-term
2.3 Dissemination and Communication
The European Federation of Crohn's and Ulcerative Colitis Associations (EFCCA) will have curtail role to
Activities to spread excellence
o dissemination and communication
o networking activities to assist knowledge transfer
Over the past decade, often with EFCCA support and advice, national self-help associations have been set up in Eastern Europe with the result that as at the end of the year 2001. The EFCCA membership has risen to 19 European National IBD Patient Associations.
2.4 Long Term Joint Research
The Consortium composed from well-known expertise they studied different genetic factors and serological disease markers of patients with Ulcerative Colitis and Crohn’s diseases. Partners all together from this field published more then 200 peer review papers.
2.4.1 Genetic Studies
Their genetic studies are including CARD15/NOD2 Mutational Analysis and Genotype-Phenotype Correlation; refinement and physical mapping of a chromosome 16q candidate region; analyses of chromosome 12 loci with Inflammatory Bowel Disease. Genetic studies on the associations between different markers (a locus on chromosome 16q, NOD2 leucin rich repeat, thiopurin S-methyltransferase) and IBD. Genetic regulation of some complement proteins (C4, Bf, C3, MBL), detection of -238 and -308 promoter polymorphismsof the TNFalpha gene. Study of endogenous antibiotic genes (defensins) as critical mediators of mucosal protection.
2.4.2 Serological Investigations
Experience with serological investigations (ANCA, ASCA) and pathogen intestinal flora (genetically determined pathogen E. coli strains). Studies on the functional and therapeutic role of pro- and anti-inflammmatory cytokines (TNFα, IL-6, IL-10, IL-12, IL-1b) and expression of adhesion molecules in inflammatory bowel disease. Studies on the role of specialised epithelial cells, particularly Paneth cells, in inflammatory bowel disease, and their influence on immune cell function, and interaction with pathogens and resident microbial flora.
Deficiencies in humoral immune response against 60 kd bacterial heat shock proteins (hsp) was also studied in IBD, study of epitope specificity and genetic regulation of anti-hsp antibodies. Measurement of complement proteins, complement activation products and antibodies against complement proteins in the sera of IBD patients and use of these measurements in differential diagnosis of Crohn's disease and ulcerative colitis.
2.4.3 Role of pathogen intestinal flora
Others studied the role of pathogen intestinal flora in IBD. Studies on regulation of steroid receptor expression in IBD. Partner will study the different changes of mucosal bacteria before and after treatment and according to various degree of inflammation. Another important point is to analyze the relationship between luminal and mucosal bacteria.
2.4.4 Surgery for IBD
The involved surgical groups have many years of experience in surgery for inflammatory bowel disease. They are studying of molecular and genetic factors (genetic polymorphisms) that predispose to post-surgical recurrence in Crohn’s disease, and the development of pouchitis after total restorative proctocolectomy in ulcerative colitis. They are also investigating thrombotic risk factors (genetic and acquired)in inflammatory bowel disease and having studies on the association between appendectomy and ulcerative colitis.
2.5 Core Group:
Organization / Country / Chief scientist / Area of excellence / Role in the project1 / Varimed Ltd. / Hungary / Dr. Sandor G. Vari / Management and coordination of EU projects, web based electronic record, eForms. / Creation of common platform for IBD research via WEB based virtual and interactive working methods Project NetBoard, web based electronic patient records, eForms for genomic and proteomic protocols. WEB based interactive education tools for young scientist and for the public.
Infonet Kranj Slovenia / Slovenia / Bostjan Bercic / Web based shared medical record, associated contractor
Vitamib Sarl. / France / Xavier Fabre / eForms, electronic database
2 / Department of Gastroenterology and Head, Laboratory of Immunogenetics, Vrije Universiteit Medical Centre, Amsterdam / the Netherlands / Professor A. Salvador Peña / Studies on associations of different genetic factors / Retrospective and prospective studies of the existing cohort.
Genetic typing for IL-1B, TGFB, IL-1RA, HLA, TNFA, LTA, FAS, NOD2/CARD15
3 / Division of Gastroenterology, Department of Medicine Cedars-Sinai Medical Center, Los Angeles, CA / USA / Professor Stephan Targan / Studies on serological disease markers of patients with ulcerative colitis and Crohn’s diseases. / Retrospective and prospective studies of the existing cohort.
Genetic studies, serological investigation, and study the role of pathogen intestinal flora.
Cedars-Sinai Medical Center, Department of Medicine, Division of Medical Genetics / Dr. Jerome I Rotter and co-workers / Studies on different genetic factors / Transcriptional tissue profiling and perform prospective clinical studies of novel gene polymorphisms as they relate to risk of IBD.
4 / Centres for Gastroenterology and Hepatology, Royal Free & University College Medical School / UK / Professor Humphrey J Hodgson and Dr Satish Keshav / Studies on the functional and therapeutic role of pro- and anti-inflammmatory cytokines and expression of adhesion molecules in inflammatory bowel disease. / Retrospective and prospective studies of the existing cohort.
Studies on the role of specialized epithelial cells, particularly Paneth cells, in inflammatory bowel disease, and their influence on immune cell function, and interaction with pathogens and resident microbial flora.
5 / 3rd Department of Internal Medicine, Semmelweis University, Budapest / Hungary. / Dr. Laszlo Bene, Prof. George Fust Dr. Agota Kovacs Dr. Zoltan Prohaszka, Dr Lilian Varga / Studies on serological disease markers of patients with ulcerative colitis and Crohn’s diseases / Retrospective and prospective studies of the existing cohort.
Humoral immune response against 60 kd bacterial heat shock proteins (hsp) in IBD, study of epitope specificity and genetic regulation of anti-hsp antibodies.
6 / Medizinische Klinik und Poliklinik, Abteilung Gastroenterologie, Universitatsklinikum Charite, Humboldt-Universitat zu Berlin / Germany / Professor Herbert Lochs / Main research interest in studying the role of cytokines. / Retrospective and prospective studies of the existing cohort. Studying the role of cytokines (TNFα, IL-6, IL-10, IL-12, IL-1b) in IBD, especially for therapy monitoring and relapse prediction. Studies on the role of pathogen intestinal flora in IBD.
7 / Division of Gastroenterology, Robert Bosch Krhaus
And University of Hohenheim, Stuttgart / Germany / Professors Eduard F. Stange and
C. Bode / Strong experience with therapeutical application of different drugs. / Retrospective and prospective studies of the existing cohort.
Studies on intestinal defensins probiotics, cytokines and heat-shock protein expression.
8 / Department of
Internal Medicine I University of
Regensburg
93042 Regensburg / Germany /
Professor Dr. Jürgen Schölmerich
Dr. Gerhard Rogler
/ Core facility „Molecular Immunologic markers in IBD” in the German IBD-Competence Network, data-banking, serum-bank, data-management, horizontal and vertical knowledge transfer / Study the role of genetic polymorphisms for the pathogenesis of IBD in specific primary intestinal cell populations (macrophages, epithelial cells). Development of new treatment strategies from the molecular analysis of IBD-mucosa associated macrophages. Prospective studies of the cohort within the planned network Gene profiling in isolated specific cell populations und treatment conditions9 / University Bologna, Department of Gastroenterology / Italy / Professor Massimo Campieri / Study the different changes of mucosal bacteria before and after treatment. / Retrospective and prospective studies of the existing cohort. Study the different changes of mucosal bacteria before and after treatment and according to various degree of inflammation. Analyze the relationship between luminal and mucosal bacteria.
10 / University Hospital Heraklion, Department of Gastroenterology Heraklion, Crete / Greece / Dr. Ioannis Koutroubak / Experience with serological markers of IBD (pANCA, ASCA, YKL-40, VAP-1, Laminin). / Studies on thrombotic risk factors (genetic and acquired) in inflammatory bowel disease. Studies on the association between appendectomy and ulcerative colitis.
11 / Unidad de Enfermedad Inflamatoria Intestinal, Servicio Aparato Digestivo, Hospital Clínico de San Carlos Madrid / Spain / Dr. Julio García-Paredes / Studies on serological disease markers of patients with IBD. / Genetic studies, serological investigation, and studies the role of pathogen intestinal flora.
12 / Servicio de Cirugía General y Digestiva, Instituto Catalán de Oncología, Ciudad Sanitaria y Universitaria de Bellvitge, Hospitalet del Llobregat, Barcelona / Spain / Dr Javier de Oca,
Dr Juan Martí Ragué,
Dr Gabriel Capella / Many years of experience in surgery for inflammatory bowel disease. / Study of molecular and genetic factors (genetic polymorphisms) that predispose to post-surgical recurrence in Crohn’s disease and the development of pouchitis after total restorative proctocolectomy in ulcerative colitis.
13 / European Federation of Crohn's and Ulcerative Colitis Associations (EFCCA)Bearwood, Bournemouth / UK / Mr. Rod Mitchell / Support and advice, 19 European National self-help associations. / Dissemination and communication, networking activities to assist knowledge transfer to the public and educate patients.
q INTEGRATION AND STRUCTURING EFFECT: The means by which the Network of Excellence will have a structuring and integrating effect on European research and assist in spreading European scientific excellence