Functional Analysis of p53 Polymorphic Variants - Diversity Supplement

p53 多态性变体的功能分析 - Diversity Supplement

• 批准号: 10818904
• 负责人: Maureen E. Murphy
• 金额: $ 4.37万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818904
• 关键词: African; African American; African ancestry; Antibodies; BAX gene; Binding; CDKN1A gene; Cancer cell line; Cell Death; Cell Death Induction; Cells; Collaborations; Consensus; Cytosol; Data; Elements; Environment; Fluorescent Dyes; Fostering; Fox Chase Cancer Center; Genes; Genetic Transcription; Germ-Line Mutation; Goals; Housekeeping; Human; Immersion; Immunofluorescence Immunologic; Immunoglobulin G; In Vitro; Individual; Knowledge; Laboratories; Lamin Type A; Lead; Ligation; MDM2 gene; Malignant neoplasm of ovary; Membrane Potentials; Mitochondria; Molecular Conformation; Monitor; Mus; Mutate; Mutation; Null Lymphocytes; PMAIP1 gene; Parents; Pathway interactions; Pennsylvania; Pharmaceutical Preparations; Population; Prognosis; Proteins; Publishing; RNA; Research; Research Personnel; Research Project Grants; SKOV3 cells; Series; Serous; Small Interfering RNA; TP53 gene; Talents; Temperature; Testing; The Wistar Institute; Time; Training; Transactivation; Treatment Efficacy; Tumor Suppressor Genes; Underrepresented Populations; United States; Universities; Variant; Visualization; Work; bak protein; cancer cell; cancer prevention; cancer risk; cancer therapy; cytotoxic; genetic variant; graduate student; meetings; mitochondrial membrane; mutant; neoplastic cell; novel; novel therapeutics; parent grant; personalized medicine; pro-apoptotic protein; programs; small molecule; summer research; trafficking; triple-negative invasive breast carcinoma; tumor; young woman

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.

项目概要 这是对 R01 CA102184 的补充请求，以培训才华横溢的毕业生 Maya Foster 女士 宾夕法尼亚大学学生在威斯塔研究所跟随 Maureen Murphy 博士学习 一种新发现的化合物，称为 SM26.1，可与突变型 p53 结合并在野生条件下稳定该蛋白质 该研究与母体 R01 相关，最近发现了两种不同的构象。 p53 肿瘤抑制基因 P47S (Pro47Ser) 和 Y107H (Tyr107His) 的种系变体具有 可能错误折叠成突变构象，从而增加人类患癌症的风险 这些发现引发了玛雅的想法，看看是否在我们的实验室中发现了化合物。 Fox Chase 癌症中心的合作者 John Karanicolas 有潜力“重新折叠”突变体 p53， 在研究中，Maya 将 P47S 和 Y107H 变体转化为野生型构象。 将在威斯塔学院享受充满活力的学院环境，并参加长期举办的活动 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拉尼科拉斯实验室的合作 福克斯·蔡斯（Fox Chase）在她的研究项目中选择将重点放在卵巢癌上。 这种肿瘤类型 100% 的情况下都会发生 p53 突变，预后较差，急需新的治疗方法 专注于卵巢癌的决定使玛雅能够参加我们的计划会议。 卵巢癌 P01，其中包括来自 Penn 的顾问和来自 Wistar、Penn、Fox 的研究人员 蔡斯癌症中心和托马斯杰斐逊大学在威斯塔研究所举行的每月会议。 该提案的两个目标将确定这种新型药物的作用机制和治疗功效 p53 重折叠化合物。