Estrogen receptor mediated reprogramming of prostate in BPH

前列腺增生症雌激素受体介导的前列腺重编程 保罗·S Cooke and Gail S Prins，多PI 摘要 在关键发育期暴露于雌激素可以永久地重新编程前列腺 腺体，导致成年期生长异常，包括基质和上皮增生，良性 腺瘤和慢性前列腺炎。因此，我们认为，早期生活中的雌激素暴露可能是一个 老年男性良性前列腺增生（BPH）的易感因素。过去的工作已经确定， 表观遗传修饰支持前列腺的发育重编程;然而， 导致这种表观基因组重组原因尚不清楚。我们以前的研究表明，雌激素受体1（ESR 1; 也称为ERα）对于这种重编程是必需的和足够的;然而，不同的信号通路 通过膜ESR 1（mESR 1）或核ESR 1（nESR 1）作用引发的疾病尚未阐明。我们 新发表的初步数据现在揭示了mESR 1在正常男性生殖系统中的重要作用。 发育和生育力，以及正常前列腺对发育雌激素化的反应。此外，A 最近的一份报告发现，重要的表观遗传变化可能导致某些基因的过度反应， 参与生长和细胞增殖，可以通过mESR 1信号级联启动， 前列腺在这种情况下，拟议研究的目标是描述mESR 1和 nESR 1介导的发育雌激素重编程，并确定“非基因组”的途径， mESR 1重新编程腺体内的表观基因组记忆，包括前列腺上皮干细胞。在此我们 将采用创新方法，通过利用新开发的 正常表达nESR 1但缺乏mESR 1信号传导的敲入小鼠模型（仅有核的ESR 1小鼠; NOER）或表达mESR 1及其下游信号通路但缺乏nESR 1（H2 NES小鼠）。 这些强大而独特的新模型使我们能够采取直接的实验方法来梳理出 ESR 1在每个隔室中的特定作用及其对表观遗传印记的下游效应物， 前列腺，这在以前是不可能的。为实现这些目标，提出了三个具体目标 目标.目的1：确定mESR 1是否是雌激素驱动的发育所必需的和/或足够的。 前列腺重编程目的2：识别参与雌激素诱导的表观遗传印记的信号级联。 目的3：阐明mESR 1和nESR 1在前列腺干/祖细胞重编程中的作用。的 拟议的研究将填补关于mESR 1和nESR 1在前列腺中的不同作用的知识空白， 发展和拓宽前列腺中雌激素印迹的机制基础。在一起，结果 将提供新的和临床相关的见解，雌激素信号的作用，通过mESR 1 和nESR 1在驱动BPH中的作用，并为未来的药物发现策略提供信息， 前列腺中的雌激素信号

ESTROGEN RECEPTOR MEDIATED REPROGRAMMING OF THE PROSTATE IN BPH Paul S. Cooke and Gail S Prins, Multi-PIs Abstract Exposure to estrogens during critical developmental periods can permanently reprogram the prostate gland, resulting in growth abnormalities in adult life that include stromal and epithelial hyperplasia, benign adenomas and chronic prostatitis. As such, we propose that early-life estrogenic exposures may be a predisposing factor for benign prostatic hyperplasia (BPH) in aging males. Past work has established that epigenetic modifications underpin developmental reprogramming of the prostate; however, the pathways that lead to this epigenomic reorganization are unclear. We previously showed that estrogen receptor 1 (ESR1; also known as ERα) is essential and sufficient for this reprogramming; however, distinct signaling pathways initiated through membrane ESR1 (mESR1) or nuclear ESR1 (nESR1) actions have not been clarified. Our new published and preliminary data now reveal essential roles for mESR1 in normal male reproductive development and fertility, as well as the normal prostatic response to developmental estrogenization. Further, a recent report found that important epigenetic changes that could lead to hyperresponsivity of certain genes involved in growth and cell proliferation can be initiated through mESR1 signaling cascades in the developing prostate gland. In this context, the goals of the proposed research are to delineate relative roles of mESR1 and nESR1 in mediating developmental estrogen reprogramming and to identify “nongenomic” pathways utilized by mESR1 to reprogram epigenomic memory within the gland, including prostate epithelial stem cells. Herein, we will take an innovative approach to directly interrogate mESR1 and nESR1 actions by utilizing newly developed knock-in mouse models that express nESR1 normally but lack mESR1 signaling (nuclear-only ESR1 mouse; NOER) or that express mESR1 and its downstream signaling pathways but lack nESR1 (H2NES mouse). These powerful and unique new models allow us to take a direct experimental approach to tease out the specific role(s) for ESR1 in each compartment and their downstream effectors on epigenetic imprinting in the prostate, which has previously not been possible. Three Specific Aims are proposed to accomplish these goals. Aim 1: Establish whether mESR1 is necessary and/or sufficient for estrogen-driven developmental prostate reprogramming. Aim 2: Identify signaling cascades involved in estrogen-induced epigenetic imprinting. Aim 3: Elucidate the roles of mESR1 and nESR1 in reprogramming prostate stem/progenitor cells. The proposed studies will fill knowledge gaps on the differential roles of mESR1 and nESR1 in prostate development and broaden the mechanistic basis for estrogenic imprinting in the prostate. Together, the results will provide new and clinically relevant insights regarding the role of estrogen signaling through both mESR1 and nESR1 in driving BPH and inform future drug discovery strategies that can target membrane-initiated estrogen signaling in the prostate.