Genetic and Dietary Interactions in MMR Deficient Colon Tumorigenesis

MMR 缺陷性结肠肿瘤发生中的遗传和饮食相互作用

• 批准号: 10095460
• 负责人: LEONARD H AUGENLICHT
• 金额: $ 16.75万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-05 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10095460
• 关键词: Automobile Driving; CRISPR/Cas technology; Calcium; Carbon; Carcinoma; Cellular biology; Cholecalciferol; Choline; Collaborations; Colon; Colon Carcinoma; Colonic Neoplasms; Complex; Consumption; DNA; Data; Developed Countries; Development; Diet; Diet Habits; Diet Modification; Dietary Component; Dietary Factors; Disease; Early Diagnosis; Environment; Epigenetic Process; Epithelial Cells; Experimental Designs; Fatty acid glycerol esters; Fiber; Folic Acid; Frequencies; Funding; Gastrointestinal Neoplasms; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Genetic Transcription; Goals; Grant; Hereditary Nonpolyposis Colorectal Neoplasms; Histopathology; Human; Individual; Inherited; Intervention; Intestines; Investigation; Link; Lymphoma; Metabolism; Methionine; Methodology; Methods; Mismatch Repair; Modeling; Modernization; Molecular; Molecular Biology; Molecular and Cellular Biology; Mucinous; Mucous Membrane; Mus; Mutation; Nutrient; Nutritional; Pathogenesis; Pathway interactions; Population; Probability; Risk; Risk Factors; Risk Marker; Site; Small Intestines; Somatic Mutation; Specificity; Stomach; Tissues; adenoma; base; colon cancer risk; colon tumorigenesis; cost effective; experimental study; feeding; genetic pedigree; genetic risk factor; high risk; human disease; insight; intestinal epithelium; mouse genetics; mouse model; novel; nutrition related genetics; screening; single-cell RNA sequencing; stem; stem cells; tumor; tumorigenesis; villin; western diet

A novel mouse model we constructed (villin-cre, Msh2flox/flox, TgfbrII”humanized” ) faithfully recapitulates mutations and a key genetic circuit driving defective mismatch repair tumorigenesis. In this model we established feeding a higher risk purified western style diet is necessary to produce tumors in the colon rather than mainly in the small intestine, therefore completely mimicking interaction of nutritional and genetic risk factors for human colon cancer. Our goals are to: a) use an approach of partial repletion of dietary alterations to identify which components of the diet impact the development of colon tumors in this VcMshThu model; b) use single cell RNAseq, now routine in our group, to dissect the dietary induced cellular and transcriptional remodeling of the colonic mucosa by the multiple diets to determine which aspects of remodeling of the colonic mucosa by the dietary factors promote tumor development in the colon. The data will provide unprecedented understanding of which and how key common dietary components in the human western style diet of developed countries promote higher risk for colon tumor development, and the complex cellular and molecular remodeling of the colonic mucosa of the western diet and components that promote development of these tumors. The translational potential is development of much deeper understanding of mechanisms establishing risk for CRC, and thus identification of new early markers of risk. This can inform cost effective strategies for screening and more efficacious new strategies for intervention.

我们构建的一种新的小鼠模型（villin-cre，Msh 2flox/flox，Tgfbr II“人源化”）忠实地概括了 突变和驱动缺陷性错配修复肿瘤发生的关键遗传电路。在这个模型中，我们 建立喂养一个更高的风险纯化西方风格的饮食是必要的，以产生肿瘤的结肠 而不是主要在小肠中，因此完全模仿营养和 人类结肠癌的遗传风险因素。 我们的目标是：a）使用部分满足饮食改变的方法来确定 饮食的组分影响该VcMshThu模型中结肠肿瘤的发展; B）使用单一的 细胞RNAseq，现在在我们的小组常规，剖析饮食诱导的细胞和转录 通过多种饮食重塑结肠粘膜，以确定哪些方面的重塑， 结肠粘膜受饮食因素的影响促进结肠肿瘤的发展。 这些数据将提供前所未有的了解，以及如何关键的常见饮食 发达国家西式饮食中的某些成分会增加患结肠癌的风险 发展，以及西方的结肠粘膜的复杂的细胞和分子重塑。 饮食和成分，促进这些肿瘤的发展。平移势为 更深入地了解确定CRC风险的机制， 识别新的早期风险标志物。这可以为筛选和 更有效的干预新策略。