Inflammatory bowel diseases (IBD) are associated with an elevated risk for colorectal cancer. Despite constant contact with the massive population of commensal bacteria, the colonic mucosa is normally hypo- responsive to these potentially proinflammatory threats. The intestinal epithelial layer functions not only as a physical barrier but also an innate and adaptive immune barrier against commensal bacteria. The long term objective is to understand how TLR-IL-1R signaling mediates the active cross-talk between the commensal and host to maintain tolerance of the colon epithelium to the commensal bacteria. Inappropriate activation of the TLR-IL-1R signaling by commensal bacteria contributes to the pathogenesis of inflammatory bowel diseases (IBD) and colitis-associated cancer (CAC). The single immunoglobulin IL-1 receptor related molecule (SIGIRR), a negative regulator for Toll-IL-IR signaling, plays a critical role in gut homeostasis, intestinal Inflammation and colitis-associated tumorigenesis by maintaining the microbial tolerance ofthe colonic epithelium. While SIGIRR Is highly expressed In colon epithelial cells, SIGIRR expression is Induced in polarized Th2 and Th17 cells, suggesting the important role of SIGIRR in modulafing the interplay between the epithelium and Immune cells in the submucosa. These results suggest that SIGIRR funcfions as a """"""""Gate Keeper"""""""" in colon epithelial cells and as a negative """"""""Feedback Control"""""""" in T cell compartment, modulating the commensal microflora-dependent innate and adaptive immune responses. The overall hypothesis is that SIGIRR plays an important regulatory role in inflammation-induced tumorigenesis in the colon through its impact on commensal microflora-dependent homeostasis and innate and adaptive immune responses ofthe colonic epithelium. To test this hypothesis, three speciflc aims are proposed:
(Aim1) Elucidate the molecular mechanism by which SIGIRR exerts its impact on homeostasis ofthe colon epithelium;
(Aim 2) Determine the cell-type specific function of SIGIRR in the control of intestinal inflammation;
(Aim 3) Investigate the mechanism by which SIGIRR impacts on tumorigenesis in colon. To achieve the aims, one important approach is to analyze the Impact of cell-type specific SIGIRR deficiency on gut homeostasis, intestinal inflammation and colitis-associated tumorigenesis. The readouts forthe function of SIGIRR will be ranged from biochemical analyses of TLR-1L-1R signaling in primary cells to studies of innate and adaptive immune responses in vivo using colitis and colon cancer models.

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The proposed study will have a major impact on our understanding about how SIGIRR exerts its inhibitory role on the signaling events mediated by TLR-IL-1R ligands, which will result in significant advances in the field of inflammation and colonic tumorigenesis and help us to determine the potential of SIGIRR as a target for developing anti-Inflammatory and anti-cancer drugs.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cleveland Clinic Lerner
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