Elucidating Pathophysiological Mechanisms of Intestinal Inflammation

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Project Summary/Abstract To date more than 200 genetic variants are known to be associated with inflammatory bowel disease (IBD). The majority of these have been identified by genome-wide association studies (GWAS). The individual Genetic Research Centers (GRCs) and the collective NIDDK IBD Genetics Consortium have successfully interacted for the last fifteen years to lead many of these discoveries. However, despite significant progress it is still unknown how the vast majority of these variants or other risk factors lead to development of IBD and its two major subtypes - Crohn’s disease (CD) and ulcerative colitis (UC). Answering these questions is critical to advancing our knowledge of IBD pathophysiology. The University of Toronto GRC, led by Dr. Mark Silverberg, has made unique and substantial contributions in this field by virtue of its longstanding clinical and genetics expertise in IBD. Since 2002, Dr. Silverberg has established a very large, comprehensive registry of well characterized, longitudinally followed IBD patients at Mount Sinai Hospital in addition to accompanying biospecimens stored at his laboratory at the Lunenfeld- Tanenbaum Research Institute in order to facilitate research in IBD. Utilizing these resources, the UTGRC will advance the understanding of UC pathophysiology in the following ways: (1) Identify gene expression profiles and pathways that will aid in understanding the mechanisms of UC relapse and prediction of UC relapse and their regulation by miRNAs and chromatin accessibility. This will be accomplished by measuring gene expression, miRNA and chromatic accessibility profiles in the colonic tissue of UC subjects immediately prior to the onset of inflammation relative to baseline measurements. (2) Identify intestinal microbes and microbial function that precede UC relapse. This will be accomplished by determining the composition of the microbial flora adherent to the intestinal tissue as well as that of stool sampled at and comparing the same time points described in (1). (3) Continue to support the mutually agreed upon Consortium-wide studies involving elucidating the factors contributing to relapse of inflammation following surgery in CD subjects, completing the discovery of all genetic variation associated with IBD, advancing our knowledge of the functional biology of such genetic variation and to utilize these data to bring clinically meaningful tools into use to promote improved outcomes for individuals affected by IBD. These will be accomplished by patient recruitment and by bringing our significant clinical and scientific expertise to the IBDGC. This will be accomplished by ongoing clinical patient and biospecimen recruitment and by bringing significant clinical and scientific expertise to the Consortium team.