Cellular mechanisms of androgen action and androgen-response gene EAF2 in prostate cancer

前列腺癌中雄激素作用和雄激素反应基因 EAF2 的细胞机制

• 批准号: 9765227
• 负责人: Laura Ellen Pascal
• 金额: $ 11.55万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-19 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765227
• 关键词: Androgens; Award; Binding; Biological Assay; Biology; Cell Proliferation; Clinical; Collaborations; Development; Down-Regulation; Funding; Future; Gene Expression; Genes; Goals; Grant; Homeostasis; Knock-out; Knockout Mice; Laboratories; Lead; Malignant neoplasm of prostate; Mentors; Mus; NCOA2 gene; PTEN gene; Phenotype; Play; Positioning Attribute; Postdoctoral Fellow; Prostate; Prostatic Diseases; Prostatic Neoplasms; Publications; Reporting; Research; Research Assistant; Role; Scientist; Signal Transduction; Specialist; TP53 gene; Testing; Transcriptional Elongation Factors; Tumor Suppressor Proteins; Universities; Update; Urologic Diseases; Xenograft procedure; androgen sensitive; career; efficacy study; experimental study; graduate student; in vivo; inhibitor/antagonist; novel; novel strategies; post-doctoral training; professor; prostate cancer model; prostate cancer prevention; prostate carcinogenesis; response; small molecule; success; trafficking; tumor xenograft

PROJECT SUMMARY/ABSTRACT This application is for the R50 Research Specialist in the laboratory of Dr. Zhou Wang at the University of Pittsburgh. A critical need for protected stable positions for scientists who understand both the basic biology and clinical aspects of urologic diseases exists. Our goal is to fulfill this need by providing a protected position for Dr. Laura E. Pascal in pursuance of the successful completion of the current and future aims of Dr. Wang's NCI funded EAF2 grant. Dr. Wang's NCI R01 CA186780 grant, “Roles of EAF2 in androgen action in the prostate”, which is in its 20th year of funding, began in 1996 with the identification and characterization of androgen-responsive genes in the prostate and was just awarded a renewal in 2015. The original aims of the past grant were 1) to characterize the effect of U19/EAF2 knockout on prostate homeostasis; 2) to determine if U19/EAF2 knockout can induce prostate cancer in PTEN+/- mice; and 3) to determine the role of ELL2, a U19/EAF2 binding partner, in U19/EAF2 action in the prostate. The grant received MERIT status in 2011 and the updated aims were 1) to test the hypothesis that loss of U19/EAF2 does not affect undeveloped prostate naïve to androgens, 2) to continue characterization of ELL2 in U19/EAF2 action in the prostate, and 3) to determine whether, and to what extent, ELL2- and EAF2-downstream genes overlap in the prostate. The current aims are 1) to investigate EAF2 interaction with p53, 2) to determine the role of EAF2 and p53 in AR- regulated gene expression and cell proliferation, and 3) to determine the effect of concurrent loss of EAF2 and p53 on prostate carcinogenesis. Dr. Pascal is actively working on experiments from Aims 2 and 3 of this current grant and was involved in the successful completion of previous Aims. Dr. Pascal began working on ELL-associated factor 2 (EAF2), an androgen-responsive transcription elongation factor, in 2008 when she joined the Dr. Wang's lab as a post-doctoral fellow. Because of her significant contributions and success in the advancement of this project, she was appointed Research Assistant Professor in the Wang lab in 2011. Dr. Wang initially discovered EAF2 as an androgen-responsive gene, up-regulated gene 19 (U19). With the assistance of Dr. Pascal, Dr. Wang's lab has generated multiple recent observations that indicate a key role for EAF2 in androgen action and prostatic diseases. Dr. Pascal was integrally involved in the publication of several recent reports that suggest EAF2 downregulation may be associated with aggressiveness of prostate cancer. Since joining Dr. Wang's lab, she has co-authored 5 publications focused on EAF2 in the prostate and has become an expert on the EAF2 knockout mouse phenotype, murine prostate tumor models with combined loss of EAF2 and tumor suppressors PTEN and p53, as well as several prostate tumor xenografts. Additionally, she is providing support for Dr. Wang's collaboration with Dr. Paul Johnston in in vivo xenograft studies of the efficacy of novel small molecules developed to inhibit AR intracellular trafficking. We request funding for a period of 5 years, allowing us to continue to support Dr. Pascal and the completion of the EAF2 grant and the tumor xenograft studies and to meet her career goal of direct participation as well as mentoring and training of post-doctoral fellows, graduate students and technicians in this research.

项目总结/摘要 此应用程序是为R50研究专家在博士的实验室周旺在大学。 匹兹堡对于既了解基础生物学， 和泌尿系统疾病的临床方面。我们的目标是通过提供一个受保护的位置来满足这一需求 劳拉·E博士帕斯卡尔在追求的成功完成目前和未来的目标，王博士的 NCI资助的EAF 2赠款。王博士的NCI R 01 CA 186780基金，“EAF 2在雄激素作用中的作用， 前列腺”，这是在其第20个年头的资助，开始于1996年的识别和表征， 前列腺中的雄激素反应基因，并于2015年获得更新。的最初目的 过去的资助是1）描述U19/EAF 2敲除对前列腺稳态的影响; 2）确定是否 U19/EAF 2敲除可在PTEN+/-小鼠中诱导前列腺癌;和3）为了确定ELL 2的作用， U19/EAF 2结合伴侣，在前列腺中的U19/EAF 2作用中。该赠款于2011年获得MERIT地位， 更新的目的是：1）检验U19/EAF 2缺失不影响未发育前列腺的假设 未接受过雄激素治疗，2）继续表征前列腺中U19/EAF 2作用中的ELL 2，以及3） 确定ELL 2和EAF 2下游基因在前列腺中是否重叠以及重叠的程度。的 目前的目的是1）研究EAF 2与p53的相互作用，2）确定EAF 2和p53在AR中的作用。 调节基因表达和细胞增殖，以及3）确定EAF 2和 p53在前列腺癌发生中的作用帕斯卡尔博士正在积极从事目标2和3的实验。 目前的赠款，并参与了成功完成以前的目标。 博士Pascal开始研究ELL相关因子2（EAF 2），这是一种雄激素反应性转录延伸， 2008年，她以博士后研究员的身份加入了王博士的实验室。因为她的重要性 贡献和成功推进这一项目，她被任命为研究助理教授 2011年在王实验室里。Wang博士最初发现EAF 2是一种雄激素反应基因，在哺乳动物中表达上调。 基因19（U19）。在帕斯卡尔博士的协助下，王博士的实验室最近进行了多项观测， 这表明EAF 2在雄激素作用和前列腺疾病中起关键作用。帕斯卡博士与 在最近发表的几份报告中，这些报告表明EAF 2下调可能与 前列腺癌的症状自从加入王博士的实验室以来，她已经共同撰写了5篇专注于 研究前列腺中的EAF 2，并已成为EAF 2敲除小鼠表型、小鼠前列腺 具有EAF 2和肿瘤抑制因子PTEN和p53的组合缺失的肿瘤模型，以及几种前列腺癌细胞， 肿瘤异种移植物此外，她还为王博士与保罗约翰斯顿博士在 开发用于抑制AR细胞内的新型小分子的功效的体内异种移植物研究 贩卖人口我们要求提供为期5年的资金，使我们能够继续支持帕斯卡尔博士和 完成EAF 2赠款和肿瘤异种移植研究，并满足她的职业目标，直接 博士后研究员、研究生和技术人员参与以及指导和培训 这项研究。