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