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

项目摘要/摘要 本申请表面向北京大学周旺博士实验室的R50研究专家 匹兹堡。对既懂基础生物学又懂基础生物学的科学家来说，迫切需要有保护的稳定职位 泌尿系统疾病的临床方面是存在的。我们的目标是通过提供受保护的职位来满足这一需求 为劳拉·E·帕斯卡博士圆满完成王博士的当前和未来目标 NCI资助EAF2赠款。王博士的NCI R01 CA186780基金，“EAF2在雄激素作用中的作用” 前列腺癌“目前已是其资助的第20个年头，它始于1996年，最初是确定和描述 前列腺中的雄激素反应基因，并在2015年刚刚获得续签。的最初目标是 过去的资助是：1)研究U19/EAF2基因敲除对前列腺稳态的影响；2)确定 U19/EAF2基因敲除可诱发PTEN+/-小鼠前列腺癌；3)确定ELL2，a)的作用 U19/EAF2结合伴侣，参与U19/EAF2在前列腺中的作用。这笔赠款在2011年获得了优异成绩，并 更新的目标是1)检验U19/EAF2缺失不影响未发育的前列腺的假设 对雄激素的天真，2)继续表征ELL2在U19/EAF2在前列腺中的作用，以及3) 确定ELL2和EAF2下游基因是否以及在多大程度上在前列腺中重叠。这个 目前的目标是1)研究EAF2与P53的相互作用，2)确定EAF2和P53在AR中的作用。 调控基因表达和细胞增殖，以及3)确定EAF2和EAF2同时缺失的影响 P53对前列腺癌发生的影响。帕斯卡博士正在积极地进行目标2和目标3的实验 目前的赠款，并参与成功地完成了以前的目标。 帕斯卡博士开始研究ELL相关因子2(EAF2)，这是一种雄激素反应的转录延伸 2008年，她作为博士后研究员加入了王博士的实验室。因为她的重要地位 在这个项目的推进中做出的贡献和成功，她被任命为研究助理教授 2011年，在王的实验室里。王博士最初发现EAF2是一种雄激素反应基因，上调表达 基因19(U19)。在帕斯卡博士的帮助下，王博士的实验室最近产生了多个观察结果 这表明EAF2在雄激素作用和前列腺疾病中起着关键作用。帕斯卡博士参与了 在最近发表的几份报告中表明，EAF2下调可能与 前列腺癌的侵袭性。自从加入王博士的实验室以来，她与人合著了5本《聚焦》杂志 并成为研究EAF2基因敲除小鼠表型的专家 EAF2、抑癌基因PTEN和P53以及多个前列腺癌联合缺失的肿瘤模型 肿瘤异种移植。此外，她还为王博士与保罗·约翰斯顿博士在 新型抑制细胞内AR小分子的体内移植研究 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博士和 完成EAF2拨款和肿瘤异种移植研究，并实现她的职业目标 参与以及指导和培训博士后研究员、研究生和技术人员 这项研究。

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.