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: 10610847
• 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/10610847
• 关键词: Affect; Age; Aging; 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; Elements; Environment; Enzymes; Epigenetic Process; Equilibrium; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; 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; Proliferating; 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; androgen biosynthesis; biomarker identification; bisulfite sequencing; career; career development; chromatin remodeling; clinical efficacy; clinical examination; design; effective therapy; effectiveness evaluation; epigenetic regulation; experience; gain of function; 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; prototype; 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.

项目摘要/摘要 候选人：我的整体职业目标是成为衰老的独立调查员和领导者 相关的目的是关注泌尿科疾病，尤其是较低的尿路功能障碍（LUTD）。贝尼 前列腺增生（BPH）是一种主要影响男性衰老并表现为尿功能障碍的疾病。 但是，该疾病的病因是复杂且多因素的，并且衰老对骑马的影响 在当前的研究中通常不考虑环境。我工作的总体目标是检查 衰老对有助于疾病发展并识别生物标志物的性别立体骑马的影响 与疾病进展和治疗效率有关。该K01职业发展建议的目标是 为我提供成为独立调查员所需的研究经验和培训 该领域的领导者。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）鉴定和分析外周生物标志物和3）衰老类固醇的表观遗传修饰剂 马内环境。这项研究经验以及来自领先专家的心理 威斯康星大学 - 麦迪逊将为我提供成功的独立研究职业。 研究：良性前列腺增生（BPH）在50年代影响50％的男性，但大幅增加至 80多岁的男性中有90％的年度治疗费用为40亿美元。男性衰老的结果之一是改变 类固醇马烯的合成和代谢，导致循环雌激素水平升高。雌激素 通过前列腺内的雌激素受体（ER）发出信号，调节前列腺组织稳态与ERα 与凋亡的增殖和ERβ有关。当前的BPH治疗靶向 雄激素几乎没有考虑到雄激素转化为ER配体。我假设选择性ER 调节剂（SERM）可以通过ERβ激活重新建立ERα：ERβ稳态​​，并逆转 ERα介导的增殖对衰老男性BPH进展的影响。关键要素 假设将在以下具体目的中进行检验： 目标1：确定ERβ配体所需的类固醇生成酶变化的影响 在体外和体内产生前列腺增殖。 AIM 2：检查衰老对类固醇新陈代谢和活性表观遗传调节的影响。 目标3：评估Serms在衰老前列腺中限制增生的有效性。 这些目标中提出的工作旨在确定潜在的外围生物标志物，以帮助评估和 分层与年龄相关的Horsene驱动增生的BPH患者。这将允许发展 新型组合药物疗法将提高当前药物治疗的临床效率。