The role of estrogen receptor alpha in prostatic fibrosis contributing to benign prostatic hyperplasia

雌激素受体α在导致良性前列腺增生的前列腺纤维化中的作用

• 批准号: 10607151
• 负责人: Hannah Miles
• 金额: $ 3.63万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607151
• 关键词: 5 Alpha-Reductase Inhibitor; Adrenergic alpha-Antagonists; Adult; Affect; Age; Aging; Agonist; Androgens; Apoptotic; Automobile Driving; Benign Prostatic Hypertrophy; Binding; Biological; Biological Markers; Bladder; Chromatography; Clinical; Complex; Detection; Development; Diagnosis; Disease; Disease Progression; Early Diagnosis; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogen Therapy; Estrogen decline; Estrogens; Etiology; Fibrosis; Financial Hardship; Functional disorder; Goals; Growth; Healthcare Industry; Hormones; Human; Image; Investigation; Kidney Failure; Knowledge; Label; Ligands; Lower urinary tract; Mass Spectrum Analysis; Mediation; Methods; Modeling; Molecular; Monitor; Mus; Obstruction; Operative Surgical Procedures; Pathogenesis; Patients; Peptides; Play; Population; Process; Proliferating; Prostate; Prostatic; Protein Analysis; Proteins; Proteomics; Raloxifene; Research; Resolution; Role; Running; Sampling; Selective Estrogen Receptor Modulators; Serum; Signal Pathway; Signal Transduction; Smooth Muscle; Specimen; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stratification; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; Translating; Treatment Efficacy; Urinary Retention; Urination; Urine; Work; androgen biosynthesis; antagonist; biomarker panel; clinically relevant; estrogenic; experimental study; high throughput analysis; improved; in vivo; insight; instrumentation; lower urinary tract symptoms; male; mass spectrometric imaging; medicine man; men; novel; novel marker; patient population; pharmacologic; precision medicine; prevent; protein expression; receptor; receptor binding; recurrent infection; reduce symptoms; steroid hormone; therapeutic target; treatment strategy; urinary; urologic

Project Abstract Benign prostatic hyperplasia (BPH) is a disease impacting much of the aging male population, affecting 50% of men 50 and older, and increasing to 90% of men 80 and older. The etiology of BPH is complex and multifactorial, though proliferation, smooth muscle dysfunction and fibrosis within the prostate are often considered the largest contributing factors, in addition to age. Estrogen signaling via receptors (ERs) within the prostate have been shown to play conflicting roles, with ERα associated with increased proliferation while ERβ with apoptotic processes. Current BPH therapeutic strategies target androgen biosynthesis without considering that androgens are regularly converted to estrogenic ligands in the steroid hormone signaling pathway. I hypothesize that estrogen signaling within the prostate, specifically ERα activity, induces prostatic fibrosis and thus contributes to the development of lower urinary tract dysfunction (LUTD) and BPH. I aim to evaluate this hypothesis through the use of mass spectrometry (MS)-based proteomics analyses. With the development of high resolution and accurate mass instrumentation, MS has become the preferred technique for deep, targeted and global proteomic profiling investigations. In addition, the development of mass spectrometry imaging (MSI) allows for high throughput analysis of protein and peptide species in a biological tissue with no prior knowledge, thus obtaining critical spatial information of hundreds of analytes in a single imaging run. I plan to utilize the high sensitivity and selectivity of both MSI and traditional chromatography-based LC-MS/MS experiments to reach the following goals: 1) to determine if ERα agonism in mice promotes prostatic fibrosis and LUTD and 2) to uncover if loss of ERα function decreases prostatic fibrosis in vivo. Collectively, these aims will both facilitate the use of MS-based strategies in urologic research and yield novel insights into the complex roles that estrogen receptor alpha plays within the prostate.

项目摘要 良性前列腺增生（BPH）是一种影响大多数男性老龄化的疾病，影响了50％ 50岁及以上的男性增加到80岁以上的男性中的90％。 BPH的病因是复杂而多因素的， 尽管增殖，平滑肌功能障碍和前列腺内的纤维化通常被认为是最大的 除了年龄外，还会导致因素。前列腺中通过受体（ER）的雌激素信号传导已是 表现出扮演冲突的角色，ERα与增殖增加有关，而ERβ与凋亡 过程。当前的BPH治疗策略靶向雄激素生物合成，而无需考虑雄激素 定期转换为类固醇骑士信号通路中的雌激素配体。我假设这一点 前列腺内的雌激素信号传导，特别是ERα活性，诱导前列腺纤维化，因此 有助于下尿路功能障碍（LUTD）和BPH的发展。我的目标是评估这个 通过使用质谱（MS）的蛋白质组学分析来假设。随着 高分辨率和准确的质量仪器，MS已成为深层，有针对性的首选技术 和全球蛋白质组织研究。此外，质谱成像（MSI）的发展 允许对生物组织中蛋白质和肽种类进行高吞吐量分析，而没有先验的知识， 因此，在单个成像运行中获得数百个分析物的关键空间信息。我计划利用高 MSI和基于传统色谱的LC-MS/MS实验的敏感性和选择性达到 以下目标：1）确定小鼠中的ERα激动剂是否促进前列腺纤维化和LUTD，以及2） 发现ERα功能的损失是否会在体内下降前列腺纤维化。总的来说，这些目标都将促进 在泌尿外科研究中使用基于MS的策略，并对雌激​​素的复杂作用产生新的见解 受体α在前列腺内发挥作用。