Analysis of the inflammatory bowel disease susceptome and resistome using a forward genetics approach

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Inflammatory bowel diseases (IBD), including both ulcerative colitis and Crohn’s disease, are extremely variable in severity, and have strong genetic components, but do not behave as simple Mendelian traits. This suggests that environmental differences between individuals including differences in the intestinal microbiome or alternatively, the cumulative effects of genetic differences at numerous loci may determine whether the disease phenotype is present. In mice, several mutations are known to favor IBD or to inhibit intestinal inflammation. But a comprehensive picture of the pathogenesis of IBD cannot be assembled based on the limited information so far available from genetic analyses, nor can human IBD be stringently ascribed to mutations that are known to be influential in mice. Here we propose to take an unbiased, hypothesis-free view of IBD, using germline mutagenesis to analyze the phenomenon in mice. In specific aim 1, we intend to screen for mutations that cause either susceptibility or resistance to IBD on a defined genetic background using the a mouse model of IBD (the Dextran sodium sulfate (DSS) colitis model), positionally clone these mutations, and form hypotheses concerning the participation of each validated gene in the disease pathogenesis. The mutations that we create will identify candidate loci that may cause IBD disease in humans, point to potential targets for therapy and yield testable hypotheses concerning the involvement of other genes in IBD resistance or susceptibility. Furthermore, in specific aim 2, we will investigate one mutant mouse with a missense error in Mbtps1, encoding the site-1 protease (S1P), which was found to be susceptible for IBD. This proposal aims toward new discoveries about the pathogenesis of IBD, which may eventually lead to new targets or therapies.