Overview Understanding the pathogenesis of Inflammatory Bowel Diseases (IBD) represents one of the most important and unresolved challenges in both clinical and investigative digestive diseases. As a result of research advances over the past several years, including many made possible by this Center, it is now possible to formulate a central hypothesis for the pathogenesis of these disorders and to apply powerful new tools that will facilitate further advances in the next several years. The many novel aspects of our understanding of the multiple pathwavs to ulcerative colitis (UC) and Crohn's disease (CD) are based upon a comprehensive dissection of the manv complexities of mucosal biology. These advances are also based on knowledge of factors sustaining surface epithelial integrity, innate immunity, lymphocyte activation, host-microbe interaction, genetic architecture of Crohn's disease and ulcerative colitis, and functional characterization of lymphocytes and antigen presenting cell populations in the intestinal mucosa. Since the last competing application, the participating collaborating investigators in this Center for the Study of IBD (CSIBD) have made many key advances in the understanding of the processes relevant to IBD and catalyzed by CSIBD, have increased their research support. The CSIBD has achieved its original goals, primarily by expanding the infrastructural support available to a cohort of highly productive investigators, and by offering, through the awarding of pilot feasibility grants, opportunities for the initiation of new ventures in inflammatory bowel disease-related research aimed primarily at young investigators. The current proposal reflects the conviction of members of the research community at the Massachusetts General Hospital (MGH), the Beth Israel Deaconess Medical Center (BIDMC), the Massachusetts Institute of Technology (MIT), the Broad Institute of Harvard and MIT and the Tufts University Medical Center that they remain in an outstanding position to achieve integration of a broad base of investigators who study basic processes of innate and adaptive immune responses, inflammatory mediators, epithelial cell function and mucosal-microbial interaction. Specifically, Center investigators are well-positioned in the coming period to undertake novel approaches, as the CSIBD has recently initiated a collaboration with the Broad Institute that will allow CSIBD investigators access to a wide array of Broad research platforms in addition to Core services. The need for Pilot Feasibility Support (PFS) by the Boston-Cambridge IBD research communities is unabated, as evidenced by the number of applications per cycle. The Center Centers have been upgraded to offer stateof-the-art computational tools and bioinformatics support, in the coming period. Gene chip technology has now moved on from microarray to so-called deep sequencing which will be offered in the Genetics, Genomics and Molecular Biology Core both in the MGH setting and for selected projects at the Broad Institute Platform. A major focus of the next funding period will be the clinical translation of human genetics research to understand biological predisposition, to dissect biological pathways that mark disease and identify targets for drug intervention. Investigators are exploring alterations of these processes in both animal models of intestinal inflammation as well as in patients with IBD. We believe that this Center for the Study of Inflammatory Bowel Disease (CSIBD) will continue to provide a highly effective framework for promoting these interactions and a mechanism for the interface of the research community with both powerful new tools for IBD research and a large clinical investigation, patient and tissue base.