Luminal Epithelial Junctions, Polarity, and Permeability in BPH Pathogenesis

项目摘要 良性前列腺增生(BPH)是老年男性最常见的疾病之一。虽然 良性前列腺增生症不危及生命，其症状显著影响生活质量，治疗费用超过40亿美元。 每年一次。前列腺炎症是与BPH相关的一个主要因素，它可以导致间质纤维化和 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 BPH间质间质中存在管腔上皮分泌蛋白PSA 结节。此外，我们还发现黏附连接蛋白E-钙粘素在BPH组织中表达下调 在前列腺炎的大鼠模型中也是如此。这些发现引出了我们的假设 炎症通过E-钙粘附素导致上皮细胞-细胞连接中断和/或极性丧失 下调并随后将前列腺液(如PSA)渗入前列腺 间质隔间。我们建议确定PSA渗入BPH间质的机制。 完成以下特定目标：1)确定前列腺腔上皮细胞连接是否 在BPH标本中，细胞发生改变，并与PSA渗入间质间质有关；2) 确定炎症在前列腺上皮通透性增加中的作用；3)确定 E-钙粘素基因敲除/敲除对细胞连接和前列腺上皮层渗漏的影响。成功之路 以上的具体目标将明确BPH患者管腔上皮通透性的变化，为下一步的研究奠定基础 进一步探讨上皮分泌物渗入BPH间质间质的机制，以及 揭示上皮分泌物渗入间质间质在BPH发病机制中的作用。 明确导致前列腺上皮渗漏的机制和后果可能导致新的靶点 用于预防和/或治疗BPH/LUTS。

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.