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

年龄对良性前列腺增生进展中类固醇生成改变和雌激素受体激活的影响

• 批准号: 9976945
• 负责人: Teresa Liu
• 金额: $ 13.1万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9976945
• 关键词: Affect; Age; Aging; Anabolism; Androgens; Animal Model; Apoptosis; Area; Benign Prostatic Hypertrophy; Biological Assay; Biological Markers; CRISPR/Cas technology; Catabolism; Cell Line; Chromatin; Clinical; Combined Modality Therapy; Complex; DNA Methylation; Data; Development; Disease; Disease Progression; Disease stratification; Effectiveness; Elements; Environment; Enzymes; Epigenetic Process; Equilibrium; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogen receptor positive; Estrogens; Etiology; Functional disorder; Gene Expression; Genes; Glycols; Goals; Gonadal Steroid Hormones; Grant; Homeostasis; Hormone Receptor; Hormones; Human; Hyperplasia; Immunohistochemistry; In Vitro; Increased frequency of micturition; Knockout Mice; Ligands; Lower urinary tract; Maps; Mediating; Mentors; Metabolism; Methods; Methylation; Modeling; Modification; Molecular; Monitor; Mus; Patients; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Positioning Attribute; Production; Prostate; Prostatic Diseases; Quality of life; Receptor Activation; Research; Research Personnel; Resolution; Sampling; Selective Estrogen Receptor Modulators; Signal Transduction; Stanolone; Steroid biosynthesis; Steroids; Symptoms; Testing; Testosterone; Tissues; Training; Treatment Cost; Treatment Effectiveness; Treatment Efficacy; Universities; Urologic Diseases; Wisconsin; Work; age effect; age related; aged; bisulfite sequencing; career; career development; chromatin remodeling; clinical efficacy; design; effective therapy; effectiveness evaluation; epigenetic regulation; experience; genome-wide; hormone regulation; improved; in vivo; insight; loss of function; lower urinary tract symptoms; male; men; minimally invasive; molecular modeling; mouse model; novel; novel drug combination; oxysterol 7-alpha-hydroxylase; promoter; receptor; receptor expression; steroid hormone; steroid hormone metabolism; steroid hormone receptor; steroid metabolism; therapy resistant; urinary

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.

项目概要/摘要 候选人：我的总体职业目标是成为老龄化领域的独立调查员和领导者 相关领域专注于泌尿系统疾病，特别是良性下尿路功能障碍（LUTD）。 前列腺增生（BPH）是一种主要影响老年男性的疾病，表现为排尿功能障碍。 但该病病因复杂、多因素影响，且衰老对激素的影响 当前的研究通常不考虑环境。我工作的首要目标是检查环境。 衰老对性类固醇激素的影响，这些激素有助于疾病的发展并识别生物标志物 与疾病进展和治疗效果相关的 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 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) 衰老类固醇的表观遗传修饰剂 这种研究经验与领先专家的指导相结合。 威斯康星大学麦迪逊分校将为我的成功独立研究生涯提供独特的定位。 研究：良性前列腺增生 (BPH) 影响 50% 的 50 多岁男性，但急剧增加至 90% 的 80 多岁男性每年的治疗费用为 40 亿美元，男性衰老的后果之一是改变。 类固醇的合成和代谢导致循环雌激素水平升高。 通过前列腺内雌激素受体 (ER) 发出的信号通过 ERα 调节前列腺组织稳态 目前的 BPH 治疗主要针对 ERβ 的生物合成。 雄激素很少考虑雄激素转化为 ER 配体，我着迷于选择性 ER。 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。 假设将在以下具体目标中进行检验： 目标 1：确定 ERβ 配体所需的类固醇生成酶与年龄相关的变化的影响 体外和体内前列腺增殖的产生。 目标 2：检查衰老对类固醇激素代谢和活性的表观遗传调节的影响。 目标 3：评估 SERM 限制老化前列腺增生的有效性。 这些目标中提出的工作旨在识别潜在的外周生物标志物，以帮助评估和 对患有与年龄相关的激素驱动的增生的 BPH 患者进行分层，这将有助于发展。 新颖的联合药物疗法将增强当前药物治疗的临床疗效。