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

描述（由申请人提供）：动物和流行病学研究表明，饮食对癌症发病率有很大影响，饮食中钙和维生素D不足与结直肠癌风险增加有关。很少有小鼠模型模拟人类的炎症和大肠癌，然而患有胃肠道炎症（溃疡性结肠炎和克罗恩病）的人类患者患结肠癌的风险显著增加。我们的实验室开发了一种小鼠模型，在该模型中，由胆门螺杆菌感染引起的一段时间的炎症，随后是大肠浸润性癌症的发展。该模型（Smad3-/-缺陷小鼠）基于转化生长因子- β (TGFss)信号的缺陷，TGFss是人类结直肠癌中最常见的受影响的细胞途径。拟议的研究将确定缺乏维生素D的合成饮食是否会增加感染胆囊虫的易感Smad3-/-小鼠的肿瘤发生易感性，反之，补充维生素D是否会延缓或预防肿瘤的发展。这项工作将通过体外研究进行补充和扩展，旨在检查TGFss和1,25-二羟基维生素D3（维生素D的激素活性代谢物）对结肠上皮细胞和巨噬细胞中细胞增殖、存活、TGFss信号传导和基因表达的调节。与细菌感染相关的特定基因先前已通过实时PCR阵列鉴定出来，巨噬细胞和上皮细胞的原代培养方法也已开发出来。该结果将为TGFss和维生素D在预防结肠炎症和癌症中的作用机制提供见解。

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.