The chronic inflammatory bowel diseases (IBD), encompassing Crohn's disease and ulcerative colitis, are severe chronic inflammatory disorders of the gastrointestinal tract, affecting approximately 25,000 (young) individuals in the Netherlands.
Although the etiology is unknown, epidemiological studies have shown that genetic factors play a key role in the susceptibility to the disease. The responsible genes however remain elusive. Complicating factors in the search for susceptibility genes are the observed strong genetic heterogeneity (different genes leading to the same clinical phenotype) as well as clinical heterogeneity (various clinical manifestations which are believed to have a different pathogenesis). Therefore, it is unlikely, that studying unselected patients wilt lead soon to identification of the susceptibility genes.
A somewhat alternative approach, which in recent years has been applied successfully, to other complex immune-mediated diseases with a known genetic basis, is to study the genetic susceptibility in model organisms. Studying IBD in genetically well-defined animal models, in the absence of complicating genetic and clinical heterogeneity will help in the identification of genes that play a key role in the regulation of the immune response in the gut. The relevance of these findings for human IBD can be subsequently tested directly in patients. We believe that this novel approach will lead to a major advance in understanding the genetic basis of human IBD, which may be helpful in the development of radical new, rational therapeutic approaches for patients with these diseases.
The research proposal fits perfectly in the research program of the Laboratory for Gastrointestinal Immunology, (part of the 'ALIFI', the Amsterdam-Leiden Institute for Immunology), and is in part continuation, and in part an expansion of applicants' previous and current research activities.
Over the last two years, the applicant has been working on animal models for IBD at the National Instituties of Health (NIH). One of these models, induced by intrarectal instillation of 2,4,6 trinitrobenzoic sulfate, is generally accepted as a good model for human IBD, and has been extensively studied in several laboratories. Work by the applicant has led to the identification of strains of mice that are highly susceptible, and highly resistent to the disease. This creates the unique oppurtunity to identify the genes that confer susceptibility to the disease. As part of this study, a 'whole genome screen' has been initiated at the NIH, which will lead within the next year to the identification of the chromosomal location(s) that carry the susceptibility gene(s). The next phase will be the actual identification of the gene(s). As a first step, the chromosomal region carrying the susceptibility gene(s) will be narrowed. This step will be carried out at the Vrije Universiteit, and consists of 'fine mapping' the region, followed by the generation of congenic mice (i.e. mice that carry the susceptibility gene on a resistant background), which will take approximately one year. Once the chromosomal region has been narrowed to a reasonable size, the actual gene will be isolated by positional cloning, the positional candidate approach or direct sequencing, depending on the results from the previous step. During this phase, which will take an estimated two to four years, the identified gene(s) will be directly investigated in human patients. Major emphasis will be put on clinical and genetic heterogeneity. For this purpose, a large database containing detailed clinical and genetic patient information, as well as a DNA and serum bank have been established at the Vrije Universiteit over the last decade. When this approach leads to the identification of genes that play a key role in the human situation, studies will be initiated to evaluate the therapeutic applicability of these findings.
The study will be mainly conducted at the Vrije Universiteit, where all resources for this study are available. Specific parts of the study will be conducted in collaboration with the NIH. For large-scale studies in patients we can rely on several contacts with national and international hospitals. |
