Luminal epithelial junctions, polarity, and permeability in BPH pathogenesis

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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.