Control of Colonic Inflammation and Tumor Growth by TGFBeta and Dietary Vitamin D

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DESCRIPTION (provided by applicant): Animal and epidemiological studies suggest that diet strongly influences cancer incidence, and inadequate dietary calcium and vitamin D are associated with increased risk of colorectal cancer. Few mouse models mimic inflammation and large bowel cancer in humans, and yet human patients with gastrointestinal inflammation (Ulcerative Colitis and Crohn's disease) have a dramatically increased risk for developing colon cancer. Our laboratory has developed a mouse model in which a period of inflammation, induced by infection with Helicobacter bilis, is followed by development of invasive cancer in the large bowel. This model (Smad3-/- deficient mice) is based on a defect in transforming growth factor-beta (TGFss) signaling, the most commonly affected cellular pathway in human colorectal cancer. Studies proposed will determine if a synthetic diet deficient in vitamin D will increase susceptibility to tumorigenesis in susceptible Smad3-/- mice infected with H. bilis, and conversely if supplemental vitamin D will retard or prevent tumor development. The work will be complemented and extended with in vitro studies designed to examine regulation by TGFss and 1,25-dihydroxyvitamin D3 (the hormonally active metabolite of vitamin D) of cell proliferation, survival, TGFss signaling, and gene expression in colon epithelial cells and macrophages. Specific genes implicated in bacterial infection have been previously identified using real time PCR arrays, and methods for primary cultures of macrophages and epithelial cells have been developed. The results will provide insights into mechanisms of action for both TGFss and vitamin D in the prevention of colonic inflammation and cancer. PUBLIC HEALTH RELEVANCE: It has become increasingly apparent that diet and diet-related diseases such as diabetes contribute strongly to the development of colon cancer. The proposed research will examine the effects of insufficient dietary vitamin D on the incidence of bacterial- induced IBD and colon cancer in a mouse model with defective TGFb signaling, as well as the ability of supplemental vitamin D to protect against disease. The detailed understanding of dietary effects and molecular mechanisms will permit more targeted and effective therapies for treatment of these diseases.