Functional Analysis of p53 Polymorphic Variants - Diversity Supplement

项目摘要 这是对R01 CA102184的补充要求，以培训Maya Foster女士，一位才华横溢的毕业生 宾夕法尼亚大学的学生，与莫琳·墨菲博士一起在Wistar研究所学习 一种新发现的叫做SM26.1的化合物，它可以与突变型p53结合，并在野生型p53中稳定这种蛋白质。 型构象这项研究与亲本R01有关，R01最近发现， p53肿瘤抑制基因的种系变体P47S（Pro47Ser）和Y107H（Tyr107His）具有 可能错误折叠成突变构象，从而导致人类癌症风险增加 和老鼠。这些发现使玛雅产生了一个想法，即看看我们实验室发现的化合物是否 合作者，福克斯蔡斯癌症中心的约翰·卡兰尼克拉斯，有可能“重折叠”突变型p53， 包括P47S和Y107H变体，转化为野生型构象。在所描述的研究中，玛雅 我将在Wistar Institute充满活力和合议的环境中工作，并参加长期的 墨菲实验室与宾夕法尼亚大学的乔治和麦克斯韦实验室以及宾夕法尼亚大学的卡兰尼克拉斯实验室的合作。 福克斯·蔡斯对于她的研究项目，玛雅选择专注于卵巢癌， 这种肿瘤类型100%的时间发生p53突变，预后差，迫切需要新的治疗方法。 治疗专注于卵巢癌的决定允许玛雅参加我们的会议， 卵巢癌P01，包括来自宾夕法尼亚大学的临床医生和来自Wistar、Penn、Fox的研究者 大通癌症中心和托马斯杰斐逊大学，每月在Wistar研究所举行的会议。 这两个目标的建议将确定机制的行动，和治疗效果，这一新的 p53重折叠化合物。

Project Summary This is a request for Supplement to R01 CA102184 to train Ms. Maya Foster, a highly talented graduate student at the University of Pennsylvania to train with Dr. Maureen Murphy at The Wistar Institute to study a newly discovered compound called SM26.1 that binds to mutant p53 and stabilizes this protein in a wild type conformation. This research is related to the parent R01, which recently uncovered that two different germline variants of the p53 tumor suppressor gene, P47S (Pro47Ser) and Y107H (Tyr107His) have the potential to misfold into a mutant conformation and hence contribute to increased cancer risk in humans and mice. These findings led to Maya’s idea to see whether compounds uncovered in the lab of our collaborator, John Karanicolas at Fox Chase Cancer Center, had the potential to ‘refold’ mutant p53, including the P47S and Y107H variants, into a wild type conformation. In the research described, Maya will engage in a vibrant and collegial environment at The Wistar Institute, and take part in long-standing collaborations of the Murphy lab with the George and Maxwell labs at Penn, and the Karanicolas lab at Fox Chase. For her research project, Maya has selected to focus on ovarian cancer, with the knowledge that this tumor type mutates p53 100% of the time, and has poor prognosis and is in urgent need of new therapies. The decision to focus on ovarian cancer allows Maya to take part in our meetings for a planned P01 in ovarian cancer, which includes clinicians from Penn and Investigators from Wistar, Penn, Fox Chase Cancer Center and Thomas Jefferson University, in monthly meetings held at The Wistar Institute. The two aims of this proposal will identify the mechanism of action, and therapeutic efficacy, of this novel p53 refolding compound.