Genetics of Tumor Suppression by p53

项目总结 这个独立职业发展计划的目标是获得结直肠癌方面的专业知识 癌症(CRC)、人口科学和实验治疗学，重点是开发新的 结直肠癌的治疗策略，取决于p53抑癌基因TP53的状态。这个 本方案概述的培训计划将充分利用广泛的资源和科学的 Wistar研究所的专业知识，并结合了Wistar、哥伦比亚大学和 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，他们有 在学术生涯中成功指导了博士后、博士后和临床研究员。 非裔美国人是美国所有种族中结直肠癌发病率和死亡率最高的。 各州。结直肠癌中最常见的基因改变包括K-RAS、Wnt和TP53。我们已经开创了 分析不同人群中自然产生的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。通过这项提议，我的目标是 非裔美国人中存在的两种p53基因变异及其对结直肠癌进展的影响 和心理治疗。P47S变异改变P53的磷酸化和转录功能；该变异受损 对于铁性细胞死亡，含有P47S变异的敲入小鼠对各种肿瘤易感 类型，包括CRC。Y107H突变体显示P53 DNA结合域结构改变，我的 数据表明，它也具有较差的肿瘤抑制功能和转录潜力。我最近用过 CRISPR工程公司为Y107H变种创建了一个鼠标模型。 P47S和Y107H变异体共同存在于美国50多万非裔美国人中。 这项拟议的研究的目标是将这些自然产生的变体用作与生物相关的工具 用它来剖析P53的功能。我将探索以下科学目标：1)阐明机制 由此P47S变异体促进结直肠癌的发生；和2)研究 非洲特有的Y107H突变在肿瘤抑制中的作用。完成这项建议中的科学目标 我将发展我在结直肠癌和TP53变异对 癌症风险，以及更全面地了解基于TP53的靶向治疗 基因分型。我期待这项研究将对理解产生深远的影响，并最终 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.