Genetics of Tumor Suppression by p53

项目摘要 这条独立职业发展之路提案的目标是获得结直肠方面的专业知识。 癌症（CRC），人口科学和实验治疗学，重点是开发新的 CRC的治疗策略，取决于p53肿瘤抑制基因TP 53的状态。的 本建议中概述的培训计划将充分利用广泛的资源和科学的 在Wistar研究所的专业知识，并结合了在Wistar，哥伦比亚大学， 福克斯·蔡斯癌症中心我的培训将由临床和基础癌症研究人员指导， 在学术生涯中成功地指导了博士前，博士后和临床研究员。 在美国，非裔美国人的CRC发病率和死亡率是所有种族中最高的。 States. CRC中最常见的遗传改变包括K-Ras、Wnt和TP 53。我们开创 分析不同人群中自然发生的p53编码区变异，重点是 这些变异对癌症风险和癌症治疗效果的影响。我提出这个建议的目的是 非裔美国人人群中存在的两种p53基因变异及其对CRC进展的影响 和心理治疗P47 S变异体改变p53磷酸化和转录功能;该变异体受损 对于铁凋亡细胞死亡，含有P47 S变异体的敲入小鼠对多种肿瘤易感 类型，包括CRC。Y107 H变异体显示p53 DNA结合域的结构改变， 数据表明它也具有较差的肿瘤抑制功能和转录潜力。我最近用 CRISPR工程化以创建Y107 H变体的小鼠模型。 P47 S和Y107 H变体共同存在于美国超过50万非洲裔美国人中。 拟议研究的目标是使用这些自然发生的变异作为生物相关的工具 来分析p53的功能我将探讨以下科学目的：1）阐明机制 由此P47 S变体促进结肠直肠癌发展;和2）研究P47 S变体的作用。 非洲特异性Y107 H变体在肿瘤抑制中的作用完成本提案中的科学目标 我将发展我在结直肠癌和TP 53变异对结肠癌的影响方面的研究技能和知识。 癌症风险，以及获得基于TP 53的靶向治疗的更完整的理解 基因型我希望这项研究能对人类的理解产生深远的影响， 成功地消除了非裔美国人的癌症差异。

PROJECT SUMMARY The goals of this Pathway to Independence Career Development proposal are to gain expertise in colorectal cancer (CRC), population science, and experimental therapeutics, with a focus on the development of novel therapeutic strategies for CRC, dependent on the status of the p53 tumor suppressor gene, TP53. The training plan outlined in this proposal will take full advantage of the extensive resources and scientific expertise at The Wistar Institute, and incorporates training with experts at Wistar, Columbia University, and the Fox Chase Cancer Center. My training will be guided by clinical and basic cancer researchers who have successfully mentored predoctoral, postdoctoral, and clinical fellows in academic careers. African Americans have the highest incidence and mortality rates of CRC of any ethnic group in the United States. The most common genetic alterations in CRC include K-Ras, Wnt, and TP53. We have pioneered the analysis of naturally occurring coding region variants of p53 in different populations, with emphasis on the impact of these variants on cancer risk and the efficacy of cancer therapy. With this proposal I take aim at two genetic variants in p53 that exist in African American populations, and their impact on CRC progression and therapy. The P47S variant alters p53 phosphorylation and transcriptional function; this variant is impaired for ferroptotic cell death, and knock-in mice containing the P47S variant are susceptible to a variety of tumor types, including CRC. The Y107H variant shows altered structure of the p53 DNA binding domain, and my data indicate that it too has poorer tumor suppressor function and transcriptional potential. I recently used CRISPR engineering to create a mouse model for the Y107H variant. The P47S and Y107H variants together exist in over half a million African Americans in the United States. The goal of the proposed research is to use these naturally-occurring variants as biologically-relevant tools with which to dissect p53 function. I will explore the following scientific aims: 1) to elucidate the mechanisms whereby the P47S variant promotes colorectal cancer development; and 2) to investigate the role of the African-specific Y107H variant in tumor suppression. The completion of the scientific aims in this proposal will develop my research skills and knowledge in both colorectal cancer and the impact of TP53 variants on cancer risk, as well as gaining a more complete understanding of targeted therapies based upon TP53 genotype. I expect this research to have a profound impact on the understanding, and on the eventual successful elimination, of cancer disparities in African Americans.