Role of Beta-Catenin in Urinary Dysfunction

$210,544U54FY2016DKNIH

University Of Wisconsin-Madison, Madison WI

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Abstract

Many aging men suffer from lower urinary tract symptoms (LUTS). Although LUTS pathophysiology is almost certainly multi-factorial, it is often caused or exacerbated by bladder outlet obstruction (BOO) associated with benign prostatic hyperplasia (BPH). The etiology of BPH and BOO are unknown. This project is highly significant because it will uncover molecular pathways driving BPH and BOO. Our new preliminary data are consistent with the hypothesis that changing hormone levels in aging men and/or reactivation of a developmental growth-regulatory pathway mediated by beta-catenin (CTNNB1) are underlying causes of BPH and BOO. In our preliminary studies we used an innovative mouse model driven by the hormonal milieu known to be present in aging men. Hormone treatment causes prostate enlargement and urinary dysfunction. Hormone treatment also increases mouse bladder and prostate expression of WNT ligands, canonical WNT pathway target genes, and extracellular matrix constituents. The hypothesis of this project is that hormone-induced CTNNB1 activation in prostate and bladder epithelium mediates cellular and molecular changes that drive benign prostate enlargement, urinary dysfunction, and fibrosis. The hypothesis will be tested in three aims. In aim 1, we will determine whether CTNNB1 activation in mouse prostate and/or bladder independently causes cellular, molecular, and functional changes in the lower urinary tract. In aim 2, we will determine whether CTNNB1 deletion protects against hormone-induced mouse urinary dysfunction. In Aim 3, we will examine associations between expression of WNT/CTNNB1 pathway components and target genes in human symptomatic BPH. It is anticipated that successful completion of this project will identify new mechanisms (and potential new drug targets) for BPH and BOO by demonstrating that WNT signaling via CTNNB1 activates pro-fibrogenic changes in the extracellular matrix of prostate and bladder.

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