Role of CRH receptor 2 in mucosal healing during colitis

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DESCRIPTION (provided by applicant): Crohn's Disease (CD) and Ulcerative Colitis (UC), collectively known as Inflammatory Bowel Disease (IBD), are chronic relapsing inflammatory disorders of the gastrointestinal tract. While the etiology of IBD is not fully understood, it is thought to be mediated in part by a defect in the mucosal epithelium. The corticotropin- releasing hormone (CRH) family includes hormones/peptides synthesized both centrally and peripherally, affecting the function of many organs, including the intestine. Activation of CRH receptor 2 in the colonic mucosa has been shown to both promote inflammation during the acute phase of colitis and enhance mucosal repair during chronic colitis. As mucosal healing is a desired therapeutic endpoint in the treatment of colitis, we will investigate whether specific modulation of CRHR2 signaling in the colonic mucosa can limit inflammation or promote restoration of the epithelial barrier. The overall objectives of this fellowship proposal are to: () demonstrate the role of CRHR2 and its ligands in colitis-associated mucosal healing and (2) identify the molecular mechanism(s) by which the CRHR2 receptor/ligand system stimulates healing-associated responses in colonic epithelial cells. To achieve these goals, we will characterize the expression profiles of CRHR2 and its ligands CRH, Urocortin 2 and Urocortin 3 in the mouse colon during the mucosal healing phase of dextran sodium sulfate (DSS) colitis. We will also evaluate colonic cell proliferation, apoptosis and inflammatory cytokine levels in DSS-treated mice following administration of a selective CRHR2 antagonist, in CRHR2 knockout mice and in conditional intestinal epithelial cell-specific CRHR2 knockout mice. Furthermore, we will test the hypothesis that IL-6/STAT3 activity in intestinal epithelial cells mediates CRHR2-dependent mucosal healing following colitis in DSS-treated mice as well as colonic mucosal biopsies from IBD patients and matched controls. This fellowship proposal involves a combination of innovative approaches utilizing both an animal model of intestinal inflammation as well as human tissues from IBD patients. The strength and expertise of the sponsorship team and their laboratories in the proposed approaches provide a unique mentoring environment to conduct the studies, and the training plan is integral to achieving the applicant's long-term goal to succeed as an independent investigator. Furthermore, as very little is known regarding the role of colonic epithelial CRH signaling in mucosal repair, findings from the proposed aims could create potential opportunity for targeted pharmaceutical approaches to enhance mucosal healing in IBD.