Role of E-Cadherin Down-Regulation in Prostatic Inflammation and Lower Urinary Tract Dysfunction

E-钙粘蛋白下调在前列腺炎症和下尿路功能障碍中的作用

基本信息

批准号：
10564514
负责人：
Zhou Wang
金额：
$ 53.66万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2023-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10564514
关键词：
Affect Afferent Pathways Age Aging Androgen Suppression Androgens Anti-Inflammatory Agents Automobile Driving Benign Benign Prostatic Hypertrophy Bladder Cadherins Cell Line Cells Chronic Clinical Clinical Research Clinical Treatment Data Disease Down-Regulation Dutasteride E-Cadherin Electrophysiology (science)Epithelial Cells Epithelium Etiology Event Exhibits Foundations Functional disorder Future Genes Heterozygote Histologic Human Incontinence Increased frequency of micturition Inflammation Inflammatory Intercellular Junctions Knockout Mice Lower urinary tract Mediating Medical Modeling Molecular Mus Non-Steroidal Anti-Inflammatory Agents Overactive Bladder PTGS2 gene Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Prevention Proliferating Prostate Prostatic Prostatic Epithelium Proteins Quality of life Rattus Role Signal Transduction Specimen Symptoms Syndrome Testing Therapeutic Tissues Transfection Treatment Cost Urination afferent nerve age related aged androgen sensitive celecoxib cell type clinically significant cytokine experimental study insight knockout gene lower urinary tract symptoms men micturition urgency mouse model multidisciplinary novel older men overexpression preclinical study role model success symptom management therapeutic target therapy development

项目摘要

Title: Role of E-cadherin down-regulation in prostatic inflammation and lower urinary tract dysfunction Summary: Benign prostatic hyperplasia (BPH) is one of the most common disease conditions in older men. Its symptoms significantly impact quality of life and treatment costs over $4 billion annually. The proposed study will focus on histological glandular BPH and associated LUTS. About half of the men with histological BPH are asymptomatic, and not all patients with LUTS or clinical BPH have large prostate. Histological BPH can lead to clinical BPH or LUTS as men age. How histological glandular BPH leads to clinical BPH or LUTS is not clear. Our preliminary studies showed prostatic secretion is leaked into the stroma of all tested glandular BPH, reflecting compromised epithelial cell-cell junctions in BPH. This observation is consistent with down-regulation of E-cadherin, a key protein required for cell-cell junction formation, in glandular BPH specimens. To evaluate the role of E-cadherin down-regulation, we generated an inducible prostate luminal epithelial cell specific E- cadherin gene (Cdh1) knockout mouse model. In this model, Cdh1 heterozygosity caused prostatic inflammation, prostatic proliferation, and bladder overactivity, which are 3 key phenotypes associated with BPH/LUTS. Importantly, these phenotypes were developed in old but not young mice, making these mice an ideal model for this age-related disease. To explore the mechanisms of E-cadherin down-regulation in BPH, our preliminary study revealed altered/elevated androgen signaling in BPH epithelial cells and androgen suppression of E-cadherin expression in explants derived from BPH but not from normal prostate. The above preliminary data led to our hypothesis that E-cadherin down-regulation in BPH predisposes prostate to developing inflammation and subsequent bladder overactivity via afferent nerve sensitization. Based on this hypothesis, we propose the following 3 specific aims. Aim 1 will determine the molecular and cellular alterations caused by luminal epithelial E-cadherin loss in the prostate of a mouse model – role of prostatic inflammation. Aim 2 will determine the prostate-to-bladder afferent cross-sensitization mechanisms inducing bladder overactivity and the effects of COX-2 inhibition or androgen blockade in Cdh1 KO mice. Aim 3 will determine the roles of altered androgen signaling and inflammatory cytokines in E-cadherin down-regulation in BPH epithelial cells. The success of the proposed project will provide insights into the causes and effects of E- cadherin down-regulation in glandular BPH, which will help guide future studies to develop and optimize therapeutics that could restore E-cadherin expression and/or suppress prostatic inflammation and related pathways in BPH/LUTS management.

标题：E-钙粘蛋白下调在前列腺注射和尿路功能障碍中的作用概括：良性前列腺增生（BPH）是老年男性最常见的疾病疾病之一。症状每年都会显着影响生活质量和治疗质量的成本超过40亿美元。拟议的研究将重点放在组织学腺体BPH和相关的LUT上。组织学BPH的男性中约有一半是无症状，并非所有患有LUTS或临床BPH的患者均具有较大的前列腺。组织学BPH可能导致临床BPH或男性年龄。组织学腺体BPH如何导致临床BPH或LUTS尚不清楚。我们的初步研究表明，前列腺分泌被泄漏到所有测试的腺体BPH的基质中，反映了BPH中的上皮细胞连接损害。该观察结果与下调一致 E-钙粘蛋白是腺体BPH标本中细胞 - 细胞连接形成所需的关键蛋白。评估电子 - 钙粘蛋白下调的作用，我们产生了可诱导的前列腺腔上皮细胞特异性E- 钙粘蛋白基因（CDH1）基因敲除小鼠模型。在此模型中，CDH1杂合性引起了前列腺炎症，前列腺增殖和膀胱过度活动，这是3种关键表型 BPH/LUTS。重要的是，这些表型是在旧但不是年轻小鼠中开发的，使这些老鼠成为这种与年龄有关的疾病的理想模型。探索BPH中电子钙粘蛋白下调的机制，我们的初步研究表明，BPH上皮细胞和雄激素的雄激素信号转导改变/升高抑制来自BPH的外植体中的E-钙粘蛋白表达，但不是正常前列腺的抑制。以上初步数据导致了我们的假设，即e-钙粘蛋白在BPH中的下调使前列腺倾向于通过传入的神经敏感性发展创新和随后的膀胱过度活动。基于在这个假设上，我们提出以下3个特定目标。 AIM 1将确定分子和细胞小鼠模型前列腺中的腔上皮E-钙粘蛋白损失引起的改变 - 前列腺的作用炎。 AIM 2将确定诱导的前列腺到宽传入跨敏化机制 CDH1 KO小鼠中COX-2抑制作用或雄激素阻断的影响。目标3意志确定雄激素信号传导改变和炎症细胞因子在电子钙粘蛋白下调中的作用 BPH上皮细胞。拟议项目的成功将为电子的原因和影响提供见解腺体BPH中的钙粘蛋白下调，这将有助于指导未来的研究以开发和优化可以恢复电子钙粘蛋白表达和/或抑制前列腺注射及相关的治疗方法 BPH/LUTS管理中的途径。