Impact of age on altered steroidogenesis and estrogen receptor activation in benign prostatic hyperplasia progression

项目总结/摘要 候选人：我的总体职业目标是成为一名独立的调查员和领导者， 相关领域集中在泌尿系统疾病，特别是下尿路功能障碍（LUTD）。良性 前列腺增生（BPH）是一种主要影响老年男性并表现为泌尿功能障碍的疾病。 然而，该病的病因复杂，多因素和衰老对激素的影响有关 目前的研究往往不考虑环境因素。我工作的首要目标是研究 衰老对性类固醇激素的影响，有助于疾病的发展，并确定生物标志物 与疾病进展和治疗效果相关。本K 01职业发展建议书的目标是 为我提供成为独立调查员所需的研究经验和培训， 领导在外地。我的培训将针对三个关键领域：1）衰老和疾病的分子建模， 2)外周生物标志物的鉴定和分析，以及3）老化类固醇的表观遗传修饰剂 激素环境这种研究经验与来自领先专家的指导相结合， 威斯康星州-麦迪逊大学将独特的定位我一个成功的独立研究生涯。 研究：良性前列腺增生（BPH）影响50%的50多岁的男性，但在2015年急剧增加， 90%的80多岁男性每年的治疗费用为40亿美元。男性衰老的一个后果是 类固醇激素合成和代谢，导致循环雌激素水平升高。雌激素 前列腺内通过雌激素受体（ER）的信号传导与ERα一起调节前列腺组织的稳态 ERβ与细胞凋亡相关。目前的BPH治疗靶向生物合成 很少考虑雄激素转化为ER配体。我假设选择性急诊室 调节剂（SERM）可以通过ERβ激活重建ERα：ERβ稳态，并逆转 ERα介导的增殖对老年男性BPH进展的影响这其中的关键因素 将在以下具体目标中检验这一假设： 目的1：确定ERβ配体所需的类固醇生成酶的年龄相关变化的影响 在体外和体内对前列腺增殖的影响。 目的2：检测衰老对类固醇激素代谢和活性的表观遗传调节的影响。 目的3：评价SERM限制老年前列腺增生的有效性。 这些目标中提出的工作旨在鉴定潜在的外周生物标志物，以帮助评估和 将BPH患者与年龄相关的激素驱动的增生进行分层。这将有助于开发 新的组合药物疗法，将提高目前的药物治疗的临床疗效。

Project Summary/Abstract Candidate: My overall career goal is to become an independent investigator and leader in an aging related field focused on urologic diseases, especially lower urinary tract dysfunction (LUTD). Benign prostatic hyperplasia (BPH) is a disease that primarily affects aging men and manifests as urinary dysfunction. However, the etiology of the disease is complex and multifactorial and the impact of aging on the hormone environment is often not considered in current research. The overarching goal of my work is to examine the effects of aging on sex steroid hormones that contribute to the development of disease and identify biomarkers relevant to disease progression and treatment efficacy. The goal of this K01 career development proposal is to provide me with the research experience and training needed to become an independent investigator and leader in the field. My training will be targeted to three key areas: 1) molecular modeling of aging and disease, 2) identification and analysis of peripheral biomarkers, and 3) epigenetic modifiers of the aging steroid hormone environment. This research experience combined with the mentoring from leading experts at the University of Wisconsin – Madison will uniquely position me for a successful independent research career. Research: Benign prostatic hyperplasia (BPH) impacts 50% of men in their 50s but dramatically increases to 90% of men in their 80s with annual treatment costs $4 billion. One consequence of aging in males is altered steroid hormone synthesis and metabolism that leads to elevated levels of circulating estrogens. Estrogen signaling through estrogen receptors (ER) within the prostate regulate prostate tissue homeostasis with ERα associated with proliferation and ERβ with apoptosis. Current BPH treatments target the biosynthesis of androgens with little consideration for androgen conversion to ER ligands. I hypothesize that selective ER modulators (SERMs) can reestablish ERα:ERβ homeostasis through ERβ activation and reverse the impact of ERα-mediated proliferation on BPH progression in the aging male. The critical elements of this hypothesis will be tested in the following specific aims: Aim 1: Determine the impact of age-related changes in steroidogenic enzymes required for ERβ ligand production on prostate proliferation in vitro and in vivo. Aim 2: Examine the effect of aging on the epigenetic regulation of steroid hormone metabolism and activity. Aim 3: Evaluate the effectiveness of SERMs to limit hyperplasia in the aging prostate. The work proposed in these aims is designed to identify potential peripheral biomarkers to aid in assessing and stratifying BPH patients with age-associated hormone driven hyperplasia. This will allow for the development of novel combination pharmacotherapies that would enhance the clinical efficacy of current drug treatments.