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

基本信息

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
项目类别：
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

项目摘要

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) 是一种影响大部分老年男性的疾病，影响 50% 50 岁及以上的男性，并且在 80 岁及以上的男性中增加到 90% BPH 的病因复杂且涉及多种因素。尽管前列腺内的增殖、平滑肌功能障碍和纤维化通常被认为是最大的除了年龄之外，通过前列腺内的受体（ER）进行雌激素信号传导也是影响因素。 ERα 与增殖增加相关，而 ERβ 与细胞凋亡相关目前的 BPH 治疗策略以雄激素生物合成为目标，但没有考虑雄激素。在类固醇激素信号通路中定期转化为雌激素配体。前列腺内的雌激素信号传导，特别是 ERα 活性，会诱导前列腺纤维化，从而导致下尿路功能障碍 (LUTD) 和 BPH 的发展，我的目的是评估这一点。通过使用基于质谱（MS）的蛋白质组学分析的假设。凭借高分辨率和精确的质量仪器，MS 已成为深度、靶向的首选技术此外，质谱成像（MSI）的发展。允许在没有先验知识的情况下对生物组织中的蛋白质和肽种类进行高通量分析，因此，我计划利用单次成像运行中获得数百种分析物的关键空间信息。 MSI 和基于传统色谱的 LC-MS/MS 实验的灵敏度和选择性达到目标如下：1) 确定小鼠体内的 ERα 激动剂是否会促进前列腺纤维化和 LUTD；2) 揭示 ERα 功能的丧失是否会减少体内前列腺纤维化。在泌尿学研究中使用基于 MS 的策略，并对雌激素的复杂作用产生新的见解 α受体在前列腺内发挥作用。