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

项目摘要/摘要 应聘者：我的总体职业目标是成为一名独立调查员和老龄化领域的领导者 相关领域主要集中在泌尿系统疾病，特别是下尿路功能障碍(LUTD)。良性 前列腺增生症(BPH)是一种主要影响老年男性的疾病，表现为排尿功能障碍。 然而，该病的病因是复杂的和多因素的，以及衰老对激素的影响 在目前的研究中，环境往往不被考虑。我工作的首要目标是研究 衰老对性类固醇激素的影响及其生物标志物的鉴定 与疾病进展和治疗效果相关。这份K01职业发展提案的目标是 为我提供成为独立调查员所需的研究经验和培训 该领域的领先者。我的培训将针对三个关键领域：1)衰老和疾病的分子模型， 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物 荷尔蒙环境。这项研究经验结合了来自 威斯康星大学麦迪逊分校将使我在成功的独立研究生涯中独树一帜。 研究：良性前列腺增生症(BPH)影响50%的50多岁男性，但急剧增加到 90%的80多岁男性每年接受治疗的费用为40亿美元。男性衰老的一个后果是改变 类固醇激素的合成和代谢导致循环雌激素水平升高。雌激素 前列腺内雌激素受体(ER)信号通过ERα调节前列腺组织的动态平衡 与增殖相关，ER-β与细胞凋亡相关。目前治疗良性前列腺增生症的目标是生物合成 雄激素，很少考虑雄激素向ER配体的转化。我假设选择性ER 调节剂(SERM)可以通过激活ERα来重建ERβ：ERβ的动态平衡，并逆转 ERα介导的增殖对老年男性良性前列腺增生症进展的影响。其中的关键要素 假设将在以下具体目标中得到检验： 目的1：确定与年龄相关的ERβ配体所需类固醇合成酶的变化的影响 体外和体内生产对前列腺增殖的影响。 目的2：研究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在限制老年前列腺增生中的作用。 这些AIMS中提出的工作旨在识别潜在的外周生物标记物，以帮助评估和 年龄相关激素驱动的增生性前列腺增生症患者分层。这将允许开发 将提高当前药物治疗的临床疗效的新的联合药物疗法。

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.