Role of Beta-Catenin in Urinary Dysfunction

许多老年男性患有下尿路症状（LUTS）。尽管LUTS的病理生理几乎肯定是多因素的，但它通常是由与良性前列腺增生（BPH）相关的膀胱出口梗阻（BOO）引起或加重的。BPH和BOO的病因尚不清楚。这个项目非常重要，因为它将揭示驱动BPH和BOO的分子途径。我们新的初步数据与衰老男性激素水平的变化和/或由β -连环蛋白（CTNNB1）介导的发育生长调节途径的重新激活是BPH和BOO的潜在原因的假设一致。在我们的初步研究中，我们使用了一种由已知存在于老年男性体内的激素环境驱动的创新小鼠模型。激素治疗导致前列腺增大和泌尿功能障碍。激素治疗也增加了小鼠膀胱和前列腺中WNT配体、典型WNT通路靶基因和细胞外基质成分的表达。本项目的假设是激素诱导的前列腺和膀胱上皮CTNNB1激活介导细胞和分子变化，从而驱动良性前列腺增大、尿功能障碍和纤维化。这一假设将在三个方面得到检验。在目的1中，我们将确定CTNNB1在小鼠前列腺和/或膀胱中的激活是否独立导致下尿路的细胞、分子和功能变化。在目的2中，我们将确定CTNNB1缺失是否保护激素诱导的小鼠尿功能障碍。在Aim 3中，我们将研究人类症状性前列腺增生中WNT/CTNNB1通路组分与靶基因表达之间的关系。通过证明WNT信号通过CTNNB1激活前列腺和膀胱细胞外基质的促纤维化变化，预计该项目的成功完成将确定BPH和BOO的新机制（和潜在的新药靶点）。

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.