Role of E-Cadherin Down-Regulation in Prostatic Inflammation and Lower Urinary Tract Dysfunction

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Title: Role of E-cadherin down-regulation in prostatic inflammation and lower urinary tract dysfunction Summary: Benign prostatic hyperplasia (BPH) is one of the most common disease conditions in older men. Its symptoms significantly impact quality of life and treatment costs over $4 billion annually. The proposed study will focus on histological glandular BPH and associated LUTS. About half of the men with histological BPH are asymptomatic, and not all patients with LUTS or clinical BPH have large prostate. Histological BPH can lead to clinical BPH or LUTS as men age. How histological glandular BPH leads to clinical BPH or LUTS is not clear. Our preliminary studies showed prostatic secretion is leaked into the stroma of all tested glandular BPH, reflecting compromised epithelial cell-cell junctions in BPH. This observation is consistent with down-regulation of E-cadherin, a key protein required for cell-cell junction formation, in glandular BPH specimens. To evaluate the role of E-cadherin down-regulation, we generated an inducible prostate luminal epithelial cell specific E- cadherin gene (Cdh1) knockout mouse model. In this model, Cdh1 heterozygosity caused prostatic inflammation, prostatic proliferation, and bladder overactivity, which are 3 key phenotypes associated with BPH/LUTS. Importantly, these phenotypes were developed in old but not young mice, making these mice an ideal model for this age-related disease. To explore the mechanisms of E-cadherin down-regulation in BPH, our preliminary study revealed altered/elevated androgen signaling in BPH epithelial cells and androgen suppression of E-cadherin expression in explants derived from BPH but not from normal prostate. The above preliminary data led to our hypothesis that E-cadherin down-regulation in BPH predisposes prostate to developing inflammation and subsequent bladder overactivity via afferent nerve sensitization. Based on this hypothesis, we propose the following 3 specific aims. Aim 1 will determine the molecular and cellular alterations caused by luminal epithelial E-cadherin loss in the prostate of a mouse model – role of prostatic inflammation. Aim 2 will determine the prostate-to-bladder afferent cross-sensitization mechanisms inducing bladder overactivity and the effects of COX-2 inhibition or androgen blockade in Cdh1 KO mice. Aim 3 will determine the roles of altered androgen signaling and inflammatory cytokines in E-cadherin down-regulation in BPH epithelial cells. The success of the proposed project will provide insights into the causes and effects of E- cadherin down-regulation in glandular BPH, which will help guide future studies to develop and optimize therapeutics that could restore E-cadherin expression and/or suppress prostatic inflammation and related pathways in BPH/LUTS management.