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.

E-钙粘附素下调在前列腺炎和下尿路功能障碍中的作用 摘要： 良性前列腺增生(BPH)是老年男性最常见的疾病之一。它的 症状严重影响生活质量，每年的治疗费用超过40亿美元。建议进行的研究 将侧重于组织学上的腺性前列腺增生症和相关的LUT。大约一半患有组织学良性前列腺增生症的男性 无症状，并不是所有LUTS或临床BPH患者都有较大的前列腺。组织学上的良性前列腺增生症可导致 随着男性年龄的增长，临床BPH或LUTS。腺性前列腺增生症如何导致临床上的良性前列腺增生症或LUTS尚不清楚。 我们的初步研究表明，所有受试腺良性前列腺增生症的间质中都有前列腺液渗漏， 反映良性前列腺增生症中受损的上皮细胞-细胞连接。这一观察结果与下调监管是一致的 腺性前列腺增生症标本中细胞间连接形成所需的关键蛋白E-钙粘蛋白的表达。评估 E-钙粘附素的作用下调，我们产生了一种可诱导的前列腺腔上皮细胞特异性E-钙粘蛋白。 钙粘蛋白基因(Cdh1)基因敲除小鼠模型。在这个模型中，cdh1杂合子引起了前列腺 炎症、前列腺增生和膀胱过度活动，这是与 BPH/LUTS。重要的是，这些表型是在老年小鼠身上发育出来的，而不是年轻小鼠，使这些小鼠成为 这是这种年龄相关疾病的理想模型。为探讨E-钙粘素在良性前列腺增生症中下调的机制， 我们的初步研究揭示了BPH上皮细胞中雄激素信号的改变/升高和雄激素 抑制E-钙粘附素在良性前列腺增生症外植体中的表达，而不是来自正常前列腺。以上内容 初步数据支持我们的假设，即E-钙粘附素在BPH中的下调易导致前列腺癌 通过传入神经敏化发展炎症和随后的膀胱过度活动。基座 基于这一假设，我们提出了以下三个具体目标。目标1将确定分子和细胞 小鼠前列腺腔上皮E-钙粘附素缺失引起的改变--前列腺的作用 发炎。目的2将确定前列腺-膀胱传入交叉敏化机制 CDH1KO小鼠膀胱过度活动及COX-2抑制或雄激素阻断的影响。目标3将 确定雄激素信号和炎性细胞因子在E-钙粘附素下调中的作用 BPH上皮细胞。拟议项目的成功将使人们深入了解电子政务的原因和影响。 钙粘附素在腺性前列腺增生症中的下调作用，这将有助于指导未来的研究发展和优化 可恢复E-钙粘附素表达和/或抑制前列腺炎症及相关的治疗 良性前列腺增生症/下尿路结石的治疗途径。