Luminal Epithelial Junctions, Polarity, and Permeability in BPH Pathogenesis

BPH 发病机制中的管腔上皮连接、极性和渗透性

• 批准号: 9323061
• 负责人: Zhou Wang
• 金额: $ 9.24万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-11 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323061
• 关键词: Adherens Junction; Affect; Aging; Benign Prostatic Hypertrophy; Cell Line; Cell Polarity; Cells; Chronic; Clinical; Confocal Microscopy; Coupled; Development; Dextrans; Diffusion; Disease; Down-Regulation; E-Cadherin; Elderly man; Electron Microscopy; Epithelial; Epithelial Cells; Extracellular Matrix Proteins; Extravasation; Fibrosis; Fluorescein-5-isothiocyanate; Foundations; Human; Inflammation; Intercellular Junctions; Interdisciplinary Study; Knock-out; Knockout Mice; Label; Lead; Life; Living Costs; Medical; Modeling; Molecular; Mus; Nodule; Pathogenesis; Patients; Permeability; Prevention; Preventive treatment; Prostate; Prostatic; Prostatic Stroma; Proteins; Quality of life; Rattus; Reporting; Role; Societies; Specimen; Stromal Cells; Symptoms; Testing; Tight Junctions; Tissues; Treatment Cost; chemokine; cost; cytokine; inflammatory marker; insight; knock-down; lower urinary tract symptoms; mRNA Expression; men; mouse model; older men; protein E; secretory protein; success; targeted treatment

Project Summary Benign prostatic hyperplasia (BPH) is one of the most common disease conditions in older men. Although BPH is not life threatening, its symptoms significantly impact quality of life and treatment costs over $4 billion annually. Prostatic inflammation is a major factor associated with BPH, which can result in stromal fibrosis and can reduce the integrity of the epithelial barrier by altering cellular junctions. In preliminary studies, we identified the presence of luminal epithelial secretory protein, PSA, in the stromal compartment of BPH nodules. Additionally, we found that adherens junction protein E-cadherin was down-regulated in BPH tissues as well as in a rat model of prostate inflammation. These findings led to our hypothesis that prostate inflammation causes disruption of epithelial cell-cell junctions and/or loss of polarity via E-cadherin down-regulation and subsequently leakage of prostatic secretions such as PSA into the prostatic stroma compartment. We propose to determine the mechanism of PSA leakage into the BPH stroma via accomplishing the following Specific Aims: 1) To determine if cellular junctions in prostatic luminal epithelial cells are altered and associated with PSA leakage into the stromal compartment in BPH specimens; 2) To determine the role of inflammation in increased prostatic epithelial permeability; 3) To determine the effect of E-cadherin knockout/knockdown on cellular junctions and leakage of the prostate epithelial layer. The success of the above specific aims will define changes of luminal epithelial permeability in BPH, lay down a foundation to further explore mechanisms leading to leakage of epithelial secretions into BPH stroma compartment, and uncover the contribution of the epithelial secretion leaked into the stromal compartment to BPH pathogenesis. Defining the mechanisms leading to and consequences of prostatic epithelial leakage may lead to new targets for prevention and/or treatment of BPH/LUTS.

项目概要 良性前列腺增生（BPH）是老年男性最常见的疾病之一。虽然 BPH 不会危及生命，其症状会严重影响生活质量，治疗费用超过 40 亿美元 每年。前列腺炎症是与 BPH 相关的主要因素，可导致基质纤维化和 可以通过改变细胞连接来降低上皮屏障的完整性。在初步研究中，我们 确定了 BPH 基质室中存在管腔上皮分泌蛋白 PSA 结节。此外，我们发现粘附连接蛋白 E-钙粘蛋白在 BPH 组织中下调 以及前列腺炎症大鼠模型。这些发现导致我们假设前列腺 炎症通过 E-钙粘蛋白导致上皮细胞-细胞连接破坏和/或极性丧失 下调，随后前列腺分泌物（例如 PSA）渗漏到前列腺中 基质室。我们建议通过以下方式确定 PSA 渗漏至 BPH 基质的机制： 实现以下具体目标： 1) 确定前列腺腔上皮中的细胞连接是否存在 BPH 标本中细胞发生改变并与 PSA 渗漏至基质室相关； 2) 至 确定炎症在前列腺上皮通透性增加中的作用； 3) 确定效果 E-钙粘蛋白敲除/细胞连接敲低和前列腺上皮层渗漏。成功 上述具体目标将为明确BPH中管腔上皮通透性的变化，奠定基础 进一步探索导致上皮分泌物渗漏至 BPH 基质室的机制，以及 揭示上皮分泌物渗入基质室对 BPH 发病机制的贡献。 定义前列腺上皮渗漏的机制和后果可能会带来新的目标 用于预防和/或治疗 BPH/LUTS。