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炎症和下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之一。症状显着影响生活质量，并且每年的治疗费用超过 40 亿美元。将重点关注组织学腺性 BPH 和相关的 LUTS。大约一半患有组织学 BPH 的男性。无症状，且并非所有 LUTS 或临床 BPH 患者都可导致前列腺肥大。随着男性年龄的增长，临床 BPH 或 LUTS 的变化尚不清楚。我们的初步研究表明前列腺分泌物渗漏到所有测试的腺体 BPH 的基质中，反映 BPH 中上皮细胞-细胞连接受损。这一观察结果与下调一致。腺性 BPH 标本中 E-钙粘蛋白（一种细胞与细胞连接形成所需的关键蛋白）的含量。为了研究E-钙粘蛋白下调的作用，我们产生了一种可诱导的前列腺管腔上皮细胞特异性E- 钙粘蛋白基因（Cdh1）敲除小鼠模型，在该模型中，Cdh1杂合性导致前列腺癌。炎症、前列腺增生和膀胱过度活动，这是与前列腺癌相关的 3 个关键表型重要的是，这些表型是在老年小鼠而非年轻小鼠中形成的，这使得这些小鼠成为这种与年龄相关的疾病的理想模型探索 BPH 中 E-钙粘蛋白下调的机制。我们的初步研究揭示了 BPH 上皮细胞和雄激素中雄激素信号的改变/升高抑制来自 BPH 的外植体中的 E-钙粘蛋白表达，但不抑制来自正常前列腺的外植体。初步数据得出我们的假设：BPH 中 E-钙粘蛋白的下调使前列腺易于发生通过传入神经敏化发展炎症和随后的膀胱过度活动。基于这一假设，我们提出以下 3 个具体目标：目标 1 将确定分子和细胞。小鼠模型前列腺中管腔上皮 E-钙粘蛋白丢失引起的改变——前列腺的作用目标 2 将确定诱导前列腺到膀胱传入交叉敏化机制。 Cdh1 KO 小鼠的膀胱过度活动以及 COX-2 抑制或雄激素阻断的影响。确定改变的雄激素信号传导和炎症细胞因子在 E-钙粘蛋白下调中的作用 BPH 上皮细胞的成功将有助于深入了解 E- 的原因和影响。腺性 BPH 中钙粘蛋白下调，这将有助于指导未来研究的发展和优化可以恢复 E-钙粘蛋白表达和/或抑制前列腺炎症及相关的治疗方法 BPH/LUTS 管理途径。