Indoleamine 2,3 Dioxygenase in Colitis Associated Cancer

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DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic research career in gastroenterology. The PI has previous experience in laboratory investigation and is fellowship trained in gastroenterology with a focus in the inflammatory bowel diseases. He is currently expanding his scientific skills in investigation of intestinal inflammation, particularly as it relates to inflammation associated carcinogenesis. Dr William Stenson, an internationally recognized expert in laboratory investigations in intestinal inflammation has an established record of training independent scientists and will provide principle mentorship. To further promote the investigator's scientific development an advisory committee comprising of highly regarded physician scientist with expertise in intestinal inflammation as well as cancer and epithelial cell biology has been established. The research environment at the PI's institution provides a rich network of intellectual and investigational resources to support career development. The proposed research focuses on an enzyme with recognized immunomodulatory properties, Indoleamine 2,3 Dioxygenase (IDO), and its role in chronic intestinal inflammation and inflammation-associated colon-rectal cancer (CRC). The inflammatory bowel diseases and their complications lead to significant morbidity in affected individuals and their families. Colitis associated cancer is one of the most feared complications. Several lines of evidence suggest a role for IDO in these processes; however the area remains largely unexplored. IDO is seen as acting through the inhibition of lymphocyte activation. Our evidence shows that IDO is highly expressed in gut epithelial cells in response to inflammation and toll-like receptor activation. This expression of IDO in epithelial cells serves a protective function in dextran sodium sulfate colitis, a model of epithelial dysfunction which is T-cell independent. The goal of these studies is provide critical insight into the T-cell dependent and epithelial cell dependent functions of IDO in chronic colitis and colitis associated colon cancer, clarifying the potential role of therapeutic agents directed at affecting IDO activity in both colitis and malignancy of the colon. Scientific tools including knockout and transgenic mouse lines will assist in addressing the specific aims including 1) Evaluating the role of IDO in both T-cell dependent and independent models of chronic colitis 2) Determining the role of IDO in colon epithelial and cancer cell proliferation, and 3) Defining T-cell dependent & independent functions of IDO in a model of colitis associated cancer. The larger goal of the applicant and this mentored research grant is to develop the knowledge and skill sets required to become an independent investigator and ask relevant basic questions in mucosal immunology that aid in our understanding of human inflammatory diseases of the gastrointestinal tract. PUBLIC HEALTH RELEVANCE: The goal of these studies is provide critical insight into the lymphocyte dependent and epithelial cell dependent functions of IDO in chronic colitis as and colitis associated colon cancer as occurs in human Crohn's and Ulcerative Colitis. The relevance of this work is to clarifying the potential role of therapeutic agents directed at affecting IDO activity in both colitis and malignancy of the colon.