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

通过 TGFBeta 和膳食维生素 D 控制结肠炎症和肿瘤生长

• 批准号: 8213462
• 负责人: LILLIAN MAGGIO-PRICE
• 金额: $ 16.97万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213462
• 关键词: Accounting; Affect; Animals; Apoptosis; Bacterial Infections; Calcitriol; Cecum; Cell Proliferation; Cells; Coculture Techniques; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Complement; Conditioned Culture Media; Crohn' s disease; D Cells; Data; Defect; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Diet; Dietary Calcium; Disease; Distant; Elements; Epidemiologic Studies; Epithelial Cell Proliferation; Epithelial Cells; Exhibits; Gene Expression; Genes; Genetic Transcription; Growth; Helicobacter; Helicobacter Infections; Human; Immune response; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Interleukin-6; Intestinal Neoplasms; Intestines; Laboratories; Large Intestine; Ligands; Malignant Neoplasms; Malignant neoplasm of large intestine; Mediating; Methods; Modeling; Molecular; Mus; Mutate; Neoplasm Metastasis; Pathway interactions; Patients; Phenotype; Predisposition; Prevention; Regulation; Reporting; Research; Research Design; Risk; Risk Factors; Signal Transduction; Signaling Molecule; Synthetic Diet; System; Time; Tissue Sample; Tissues; Transforming Growth Factor beta; Ulcerative Colitis; Vitamin D; Work; base; bone morphogenic protein; cancer cell; cell type; cytokine; effective therapy; gastrointestinal; human disease; in vitro Model; insight; lymph nodes; macrophage; mouse model; osteogenin; paracrine; prevent; public health relevance; research study; response; tumor; tumor growth; tumorigenesis

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.

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，膳食钙和维生素D不足与结直肠癌风险增加有关。很少有小鼠模型能模拟人类的炎症和大肠癌，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。我们的实验室已经开发了一种小鼠模型，其中由胆汁螺杆菌感染诱导的一段时间的炎症，随后是大肠浸润性癌的发展。该模型（Smad 3-/-缺陷小鼠）基于转化生长因子-β（TGF β）信号传导的缺陷，这是人类结直肠癌中最常见的受影响的细胞途径。拟进行的研究将确定缺乏维生素D的合成饮食是否会增加感染H.相反，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，这些研究旨在检查TGF β和1，25-二羟基维生素D3（维生素D的代谢产物）对结肠上皮细胞和巨噬细胞中细胞增殖，存活，TGF β信号传导和基因表达的调节。先前已经使用真实的时间PCR阵列鉴定了与细菌感染有关的特定基因，并且已经开发了用于巨噬细胞和上皮细胞的原代培养的方法。这些结果将为TGF β和维生素D预防结肠炎症和癌症的作用机制提供见解。 公共卫生相关性：越来越明显的是，饮食和饮食相关的疾病，如糖尿病，对结肠癌的发展有很大的影响。拟议的研究将在TGF b信号传导缺陷的小鼠模型中检查膳食维生素D不足对细菌诱导的IBD和结肠癌发病率的影响，以及补充维生素D预防疾病的能力。对饮食效应和分子机制的详细了解将使这些疾病的治疗更有针对性和更有效。