Immune control of oncogene selection in preneoplastic colon

癌前结肠癌基因选择的免疫控制

• 批准号: 10740144
• 负责人: Haris Mirza
• 金额: $ 18.53万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-14 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740144
• 关键词: Affect; Age; Anatomy; Architecture; Bayesian Method; Blocking Antibodies; Cancer Etiology; Cancerous; Cell Proliferation; Cells; Cellular Morphology; Cessation of life; Clone Cells; Colon; Colon Carcinoma; Colonic Neoplasms; Colonoscopy; Data; Development; Diagnosis; Epithelium; Evolution; Goals; Histologic; Human; Immune; Immune system; Immunologic Surveillance; Immunoprevention; In Vitro; Incidence; Individual; Infiltration; Interleukin-10; Label; Lesion; Major Histocompatibility Complex; Malignant Neoplasms; Mentors; Molecular; Morphology; Mucous Membrane; Mus; Mutate; Mutation; Oncogenes; Oncogenic; Organoids; Pathway interactions; Patients; Physicians; Prevention strategy; Prevention therapy; Program Development; Proliferating; Regulation; Regulatory T-Lymphocyte; Reporter; Research; Research Personnel; Role; Scientist; Shapes; Signal Transduction; Supporting Cell; T cell infiltration; T-Cell Depletion; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Training Programs; Tube; Woman; Work; base; cancer initiation; career development; cell type; colon cancer prevention; cytokine; epithelial stem cell; experimental study; interleukin-10 receptor; intestinal crypt; mouse model; mutant; neoplastic; premalignant; prevent; segregation; stem cell biology; stem cells; transcriptomics; treatment strategy; tumor; tumor immunology; tumor microenvironment; tumor-immune system interactions

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.

结肠癌是通过上皮干中致癌突变的逐步积累而发生的 细胞这些突变的干细胞在健康的结肠中通过阳性选择繁殖多年， 转化成癌症在这个建议中，我的目标是解开一个免疫监视机制， 阻止健康结肠中突变干细胞的选择。BRAFV 600 E结肠癌 突变涉及近端结肠，不成比例地影响65岁以上的女性 年基于这些癌症独特的解剖学和人口学分布，我建议 BRAFV600E突变的干细胞在近端结肠中具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， BRAFV600E突变的癌症。因此，我假设调节性T细胞识别并 抑制健康结肠中BRAFV600E突变干细胞的选择。为了验证这一 假设，我已经开发了几种遗传诱导谱系追踪小鼠， 在单个结肠干细胞中诱导BRAFV 600 E突变。用这些老鼠，我将解剖 调节性T细胞用于监视 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发展。的 建议还包括在具有专业知识的导师指导下的严格培训计划 在肿瘤免疫学、干细胞生物学和癌症演变方面。完成建议 这些活动将帮助我实现成为一名独立的物理学家和科学家的目标， 研究针对结肠癌的免疫预防策略。