The Roles of IBD Associated Genes ATG16L1 and TNFSF15 in Gut Mucosal Inflammation

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DESCRIPTION (provided by applicant): Inflammatory bowel diseases (IBD) result from complex interactions between susceptibility genes, the environment, and the mucosal immune system. These interactions lead to an exaggerated immune response to the gut microbial flora. With the advent of high-throughput molecular technologies, genome wide association studies (GWAS) identified several IBD associated genes including intracellular pattern recognition sensor NOD2, autophagy genes (ATG16L1 and IRGM) and tumor necrosis factor superfamily member 15 (TNFSF15). Several recent reports show that ATG16L1 and NOD2 interact in a common pathway to affect microbial handling including sequestration of bacteria into autophagosomes, clearance of intracellular bacteria, and antigen presentation. Several studies have shown that TNFSF15 is expressed by antigen presenting cells (APC) and determines the severity of chronic gut inflammation by enhancing Th1, Th17 and Th2 responses. We demonstrated that a variety of bacteria, both pathogenic and commensal, can induce TNFSF15 expression in APC. Our unpublished data show that TNFSF15 expression can be increased by NOD2 activation and induction of autophagy, indicating an important role of bacterial processing in the induction of TNFSF15. The objective of this research proposal is to address the mechanism(s) of autophagy dependent bacterial handling in the induction of TNFSF15 expression and modulation of intestinal inflammation. We will test the hypothesis that autophagy handling of microbial organism is important for optimal TNFSF15 expression through autophagy processing of bacterial antigen leading to enhanced intestinal inflammation. Furthermore, I hypothesize that the higher level of TL1A expression will amplify inflammatory immune responses and exacerbate the severity of chronic intestinal inflammation. The following specific aims will test this hypothesis. Specific Aim 1: Determine the steps in the autophagy pathway that contribute to optimal expression of TNFSF15; Specific Aim 2: Correlate genetic CD variants of ATG16L1 and IRGM to TNFSF15 expression in human APC; Specific Aim 3: Determine the role of autophagy in epithelial cells, dendritic cells, and macrophage on the development and severity of murine chronic colitis. The significance of this research is that it will allow insight on mucosal immune responses to gut microflora that may lead to new IBD therapies.