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

• 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
• 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

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-cadherin下调在前列腺炎症和下尿路功能障碍中的作用 总结： 良性前列腺增生（BPH）是老年男性最常见的疾病之一。其 症状严重影响生活质量，每年治疗费用超过40亿美元。拟定研究 将重点关注组织学上的腺性BPH和相关的LUTS。大约一半的组织学BPH患者是 前列腺肥大是无症状的，并且并非所有患有LUTS或临床BPH的患者都具有大前列腺。组织学BPH可导致 临床BPH或LUTS。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，前列腺分泌物渗漏到所有测试的腺性BPH的基质中， 反映了BPH中受损的上皮细胞-细胞连接。这一观察结果与下调 的E-钙粘蛋白，细胞连接形成所需的关键蛋白质，在腺体BPH标本。评价 E-cadherin下调的作用，我们产生了一个可诱导的前列腺腔上皮细胞特异性E-cadherin， 钙粘蛋白基因（Cdh 1）敲除小鼠模型。在该模型中，Cdh 1杂合性导致前列腺 炎症、前列腺增生和膀胱过度活动，这是与前列腺增生相关的3种关键表型。 BPH/LUTS。重要的是，这些表型是在老年小鼠而不是年轻小鼠中形成的，使这些小鼠成为 是这种与年龄相关疾病的理想模型。探讨E-cadherin在BPH中表达下调的机制， 我们的初步研究揭示了BPH上皮细胞中雄激素信号的改变/升高， 抑制来源于BPH而不是来源于正常前列腺的外植体中的E-钙粘蛋白表达。上述 初步数据使我们假设BPH中E-钙粘蛋白的下调使前列腺易于发生 通过传入神经敏感化发展炎症和随后的膀胱过度活动。基于 基于这一假设，我们提出了以下3个具体目标。目标1将确定分子和细胞 小鼠模型前列腺腔上皮E-钙粘蛋白丢失引起的改变-前列腺上皮细胞的作用 炎症目的2：探讨前列腺-膀胱传入交叉致敏机制 膀胱过度活动和考克斯-2抑制或雄激素阻断在Cdh 1 KO小鼠中的作用。目标3将 确定改变的雄激素信号传导和炎性细胞因子在E-cadherin下调中的作用， BPH上皮细胞。拟议项目的成功将使人们深入了解E- 钙粘蛋白在腺体BPH中的下调，这将有助于指导未来的研究，以开发和优化 可以恢复E-钙粘蛋白表达和/或抑制前列腺炎症和相关疾病的治疗剂 BPH/LUTS管理的途径。