Immune control of oncogene selection in preneoplastic colon

结肠癌是通过上皮干细胞中致癌基因突变的逐步积累而发展起来的 细胞。这些突变的干细胞通过阳性选择在健康的结肠中繁殖了多年 转化为癌症。在这项提议中，我的目标是解开一种免疫监视机制 这阻止了在健康的结肠中选择突变的干细胞。携带BRAFV600E基因的结肠癌 突变累及近端结肠，并不成比例地影响65岁以上的女性 好几年了。基于这些癌症独特的解剖和人口分布，我建议 BRAFV600E突变的干细胞在近端结肠有很强的选择性优势。 调节性T细胞是结肠干细胞微环境的一部分，也是大量渗透的 BRAFV600E突变的癌症。因此，我假设调节性T细胞识别和 抑制健康结肠中BRAFV600E突变干细胞的选择。为了测试这一点 假设，我已经培育了几只基因可诱导的谱系追踪小鼠，特别是 在单个结肠干细胞中诱导BRAFV600E突变。利用这些老鼠，我将解剖 调节性T细胞用来监视病毒的分子机制 BRAFV600E突变的干细胞。确定调节性T细胞在癌基因中的作用 选择将导致针对结肠癌的免疫预防疗法的开发。这个 提案还包括在具有专业知识的导师的指导下进行严格的培训计划 在肿瘤免疫学、干细胞生物学和癌症进化方面。完成拟议的 这些活动将帮助我实现成为一名独立的内科科学家的目标， 研究结肠癌的免疫预防策略。

Colon cancers develop by stepwise accumulation of oncogenic mutations in epithelial stem cells. These mutated stem cells multiply by positive selection in healthy colon for years before transforming into cancers. In this proposal I aim to unravel an immune surveillance mechanism that prevents selection of mutated stem cells in healthy colon. Colon cancers with BRAFV600E mutation involve the proximal colon and disproportionately affect women above the age of 65 years. Based on the unique anatomic and demographic distribution of these cancers, I propose that BRAFV600E mutated stem cells have a strong selective advantage in the proximal colon. Regulatory T cells are part of the colonic stem cell microenvironment and, also heavily infiltrate BRAFV600E mutated cancers. Thus, I hypothesize that the regulatory T cells recognize and suppress the selection of BRAFV600E mutated stem cells in the healthy colon. To test this hypothesis, I have developed several genetically inducible lineage tracing mice that specifically induce BRAFV600E mutation in a single colonic stem cell. Using these mice, I will dissect the molecular mechanisms employed by regulatory T cells to perform surveillance against BRAFV600E mutated stem cells. Establishing the role of regulatory T cells in oncogene selection will lead to development of immune-prevention therapies against colon cancers. The proposal also includes a rigorous training program under the guidance of mentors with expertise in tumor immunology, stem cell biology and cancer evolution. Completion of the proposed activities will help me realize my goal of becoming an independent physician-scientist, investigating immune preventive strategies against colon cancer.