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

项目摘要 良性前列腺增生症(BPH)是一种影响大部分老年男性人口的疾病，影响50%的 50岁及以上的男性，80岁及以上男性的比例上升至90%。前列腺增生症的病因是复杂的和多因素的， 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 除年龄外，还有其他促成因素。通过前列腺内的受体(ER)传递的雌激素信号已被 显示出相互冲突的作用，ERα与增殖增加有关，而ERβ与细胞凋亡有关 流程。目前的BPH治疗策略以雄激素的生物合成为目标，而没有考虑雄激素 在类固醇激素信号通路中经常被转化为雌激素配体。我假设 前列腺内的雌激素信号，特别是ERα活性，诱导前列腺纤维化，从而 促进下尿路功能障碍(LUTD)和良性前列腺增生症的发展。我的目标是评估这一点 假说通过使用基于质谱仪(MS)的蛋白质组学分析。随着……的发展 高分辨率和精确的质量检测，MS已经成为深度、靶向的首选技术 和全球蛋白质组图谱研究。此外，质谱学成像(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多肽种类进行高通量分析， 从而在单次成像运行中获得数百个分析物的关键空间信息。我计划利用最高的 MSI和传统色谱型LC-MS/MS实验的灵敏度和选择性 以下目标：1)确定ER-α激动剂是否促进小鼠的前列腺纤维化和LUTD2) 揭示体内ERα功能缺失是否会减少前列腺纤维化。总的来说，这些目标都将促进 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 受体阿尔法在前列腺内发挥作用。

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.