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: 10002344
• 负责人: Zhou Wang
• 金额: $ 21.87万
• 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: 2016-09-22 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002344
• 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 Attachment; Epithelial Cells; Epithelium; Extracellular Matrix Proteins; Extravasation; Fibrosis; Fluorescein-5-isothiocyanate; Foundations; Human; Inflammation; Intercellular Junctions; Interdisciplinary Study; Knock-out; Knockout Mice; Label; Lead; Medical; Modeling; Molecular; Mus; Nodule; Pathogenesis; Patients; Permeability; Prevention; Preventive treatment; Prostate; Prostatic; Prostatic Epithelium; Prostatic Stroma; Proteins; Quality of life; Rattus; Reporting; Research; Role; Societies; Specimen; Stromal Cells; Stromal Hyperplasia; Symptoms; Testing; Tight Junctions; Tissues; Treatment Cost; Universities; chemokine; cost; cytokine; inflammatory marker; insight; knock-down; lower urinary tract symptoms; mRNA Expression; men; mouse model; older men; programs; 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.

项目摘要 良性前列腺增生（BPH）是老年男性最常见的疾病疾病之一。虽然 BPH并不威胁生命，其症状显着影响生活质量和治疗质量，成本超过40亿美元 每年。前列腺炎症是与BPH相关的主要因素，这可能导致基质纤维化和 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 鉴定出在BPH的基质区室中腔内上皮分泌蛋白PSA的存在 结节。此外，我们发现粘附蛋白E-钙粘着蛋白在BPH组织中下调 以及在大鼠的前列腺炎症模型中。这些发现导致了我们的假设 炎症会导致上皮细胞 - 细胞连接和/或通过E-钙粘着蛋白失去极性 下调和随后将PSA等前列腺分泌物（例如PSA）泄漏到前列腺中 基质室。我们建议通过通过 完成以下特定目的：1）确定前列腺上皮中的细胞连接是否是否 细胞会改变并与BPH标本中基质隔室泄漏到基质隔室相关。 2）到 确定炎症在增加前列腺上皮通透性中的作用； 3）确定效果 E-钙粘蛋白敲除/敲除对前列腺上皮层的泄漏和泄漏。成功 上述特定目的将定义BPH中腔上皮渗透性的变化，奠定基础 进一步探索机制，导致上皮分泌泄漏到BPH基质室中，并 发现上皮分泌的贡献被泄漏到基质室对BPH发病机理的贡献。 定义导致前列腺上皮泄漏的机制和后果可能导致新目标 用于预防和/或BPH/LUTS的治疗。