Functional Analysis of p53 Polymorphic Variants - Diversity Supplement

项目摘要 这是对R01 CA102184的补充申请，以培养一位才华横溢的毕业生玛雅·福斯特女士 宾夕法尼亚大学的学生在Wistar研究所跟随Maureen Murphy博士学习 一种新发现的名为SM26.1的化合物，它与突变的p53结合，并在野生动物中稳定这种蛋白质 类型构象。这项研究是与亲本R01有关的，最近发现两个不同的 P53抑癌基因的胚系变体P47S(Pro47Ser)和Y107H(Tyr107His)具有 有可能错误折叠成突变构象，从而增加人类患癌症的风险 还有老鼠。这些发现导致了玛雅的想法，看看在我们的实验室中发现的化合物 合作者，福克斯·蔡斯癌症中心的约翰·卡拉尼科拉斯，有可能重新折叠突变的p53， 包括P47S和Y107H变异体，形成野生型构象。在所描述的研究中，玛雅 将在Wistar Institute参与一个充满活力和合作的环境，并参加长期的 墨菲实验室与宾夕法尼亚大学的George和Maxwell实验室以及Karanicolas实验室的合作 福克斯·蔡斯。在她的研究项目中，玛雅选择了专注于卵巢癌，因为她知道 这种肿瘤类型100%发生P53突变，预后差，迫切需要新的 治疗。专注于卵巢癌的决定让玛雅可以参加我们计划好的会议 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的研究人员 大通癌症中心和托马斯·杰斐逊大学，在维斯塔尔研究所举行的每月会议上。 这项提议的两个目的将确定这部小说的作用机制和治疗效果。 P53复性化合物。

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.