Genetic and Dietary Interactions in MMR Deficient Colon Tumorigenesis

我们构建的一种新的小鼠模型(Villin-cre，Msh2flx/Flox，TgfbrII“人性化”)如实地概括了 突变和驱动缺陷错配修复肿瘤发生的关键遗传电路。在此模型中，我们 公认的喂养高风险的纯净西式饮食是产生结肠肿瘤所必需的 而不是主要在小肠中，因此完全模仿了营养和 人类结肠癌的遗传危险因素。 我们的目标是：a)使用部分补充饮食改变的方法来确定 在VcMshThu模型中，饮食的成分影响结肠肿瘤的发展；b)使用单一 细胞RNAseq，现在是我们组的常规，来分析饮食诱导的细胞和转录 通过多重饮食对结肠粘膜的重塑来确定哪些方面的重塑 结肠粘膜受饮食因素的影响，促进了结肠肿瘤的发展。 这些数据将提供对哪些以及如何关键的共同饮食的前所未有的理解 发达国家人类西式饮食中的成分会增加患结肠癌的风险 西医结肠粘膜的发育及复杂的细胞和分子重塑 饮食和促进这些肿瘤发展的成分。翻译的潜力是 对建立儿童权利公约风险的机制有更深入的了解，从而 识别新的风险早期标志物。这可以为具有成本效益的筛查和 更有效的干预新策略。

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.