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，饮食强烈影响癌症发病率，饮食中钙和维生素D不足与结直肠癌风险增加有关。很少有老鼠模型能模拟人类的炎症和结肠癌，但患有胃肠道炎症(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。我们实验室已经建立了一种小鼠模型，在该模型中，由胆汁螺杆菌感染引起的一段时间的炎症之后是大肠浸润性癌的发展。这个模型(SMAD3/缺陷小鼠)是基于转化生长因子-β(TGFss)信号的缺陷，转化生长因子-β(TGFss)是人类结直肠癌最常见的细胞通路。建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汁杆菌的敏感Smad3/-小鼠的肿瘤易感性，反之，补充维生素D是否会延缓或阻止肿瘤的发展。这项工作将得到体外研究的补充和扩展，这些研究旨在研究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细胞增殖、存活、TGFss信号和基因表达的调节。与细菌感染有关的特定基因以前已经使用实时荧光聚合酶链式反应阵列进行了鉴定，巨噬细胞和上皮细胞的原代培养方法已经开发出来。这一结果将为TGFs和维生素D在预防结肠炎和癌症方面的作用机制提供深入的见解。 公共卫生相关性：越来越明显的是，饮食和与饮食相关的疾病，如糖尿病，对结肠癌的发展有很大的促进作用。这项拟议的研究将检查饮食中维生素D不足对细菌诱导的IBD和结肠癌发病率的影响，在TGFb信号缺陷的小鼠模型中，以及补充维生素D预防疾病的能力。对饮食影响和分子机制的详细了解将为这些疾病的治疗提供更有针对性和更有效的治疗方法。

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.