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 BPH不会危及生命，其症状会显著影响生活质量，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，其可导致间质纤维化， 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 发现在BPH的间质区室中存在腔上皮分泌蛋白PSA 结节此外，我们发现粘附连接蛋白E-cadherin在BPH组织中表达下调， 以及在前列腺炎症的大鼠模型中。这些发现使我们假设前列腺 炎症通过E-钙粘蛋白引起上皮细胞-细胞连接的破坏和/或极性的丧失 前列腺分泌物如PSA的下调和随后的渗漏进入前列腺 基质区室我们建议通过以下方法确定PSA渗漏到BPH间质的机制： 实现以下具体目的：1）确定前列腺腔上皮中的细胞连接 细胞发生改变，并与PSA渗漏到BPH标本的间质室有关; 2） 确定炎症在前列腺上皮通透性增加中的作用; 3）确定 细胞连接处的E-钙粘蛋白敲除/敲低和前列腺上皮层渗漏。成功 上述具体目的之一，将为明确BPH时管腔上皮通透性的变化， 进一步探索导致上皮分泌物渗漏到BPH间质区室的机制， 揭示了前列腺上皮细胞分泌物渗漏到间质中对BPH发病的作用。 明确导致前列腺上皮渗漏的机制和后果可能会导致新的靶点 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.