Steroid Hormone Pathways Regulating BPH and LUTS

年龄是良性前列腺增生症(BPH)的主要危险因素，BPH是一种进行性疾病，发生于 随着男性年龄的增长，患病率不断上升，影响到70%的60多岁的男性和90%的80多岁的男性。 BPH严重影响生活质量，导致膀胱出口梗阻和下尿路 症状(LUT)，表现为通过前列腺的尿路流量减少和膀胱排空不全 导致尿频，特别是在夜间(夜尿症)。分子机制导致的 BPH/LUT尚不清楚，这延缓了治疗的发展。相关血清的增龄性变化 睾酮(T)和雌二醇(E2)水平与BPH/LUTS有关。T和E2是主要的贡献者 通过核受体调节基因表达的BPH/LUTS的启动和进展 (经典信号通路)或2)快速激活激活级联和改变的膜受体 细胞过程(非经典信号)。 我们的初步研究确定了一种新的范式来解释持续的前列腺平滑肌 收缩导致尿流受限和下尿路狭窄。老年BPH/LUTS三种模型的应用 T和E2水平，我们发现蛋白磷酸酶1调节因子(PPP1r)的表达一致变化， 降低或预计会降低肌球蛋白轻链磷酸酶(MLCP)的活性 前列腺平滑肌(SM)松弛和膀胱排尿。这一重要进展确定了PPP1r 蛋白质和其他SM松弛调节剂作为逆转衰老相关BPH/LUTS治疗的靶点。 在目标1中，我们将确定PPP1r蛋白和其他促进松弛途径的成员，它们是 在衰老的小鼠前列腺模型和人BPH组织/细胞培养中的差异调节。在目标2中，我们 将确定启动和维持BPH和LUTS所需的T和E2介导的途径 转基因小鼠只有经典或非经典的E2信号或只有经典的T信号。 我们的结果将为前列腺周围持续的SM收缩提供一个机制上的解释， 限制尿流和LUT，包括与年龄相关的改变所发生的排尿功能障碍 荷尔蒙水平。我们的发现将确定BPH/LUTS进展所需的途径和过程 确定LUTS治疗的新靶点。

Aging is a major risk factor for benign prostate hyperplasia (BPH), a progressive disease that occurs with increasing prevalence as men age, affecting 70% of men in their sixties and 90% of men in their eighties. Quality of life is severely impacted by BPH, which leads to bladder outlet obstruction and lower urinary tract symptoms (LUTS) presenting as reduced flow through the prostatic urethra and incomplete bladder emptying resulting in more frequent urination, especially at night (nocturia). Molecular mechanisms responsible for BPH/LUTS are unclear, which has delayed treatment development. Age-related changes in relative serum testosterone (T) and estradiol (E2) levels are associated with BPH/LUTS. T and E2 are major contributors to BPH/LUTS initiation and progression that act through 1) nuclear receptors to regulate gene expression (classical signaling pathway) or 2) membrane receptors that rapidly activate kinase cascades and alter cellular processes (nonclassical signaling). Our preliminary studies identify a new paradigm to explain sustained prostatic smooth muscle contraction that causes restriction of urine flow and LUTS. Using 3 models of BPH/LUTS with aged levels of T and E2, we found consistent altered expression of protein phosphatase 1 regulators (PPP1r) that decrease or are predicted to decrease activity of myosin light chain phosphatase (MLCP) required for prostatic smooth muscle (SM) relaxation and bladder voiding. This important advance identifies PPP1r proteins and other SM relaxation regulators as targets for therapies to reverse aging associated BPH/LUTS. In Aim 1, we will identify PPP1r proteins and other members of the relaxation promoting pathway that are differentially regulated in aged mouse prostate models and human BPH tissues/cell cultures. In Aim 2, we will identify the T- and E2-mediated pathways required to initiate and sustain BPH and LUTS by using our transgenic mice having only classical or only nonclassical E2 signaling or only classical T signaling. Our results will provide a mechanistic explanation for sustained SM contraction around the prostatic urethra, restriction of urine flow and LUTS including voiding dysfunction that occurs with aging-related altered hormone levels. Our findings will identify pathways and processes required for BPH/LUTS progression and identify new targets for LUTS therapies.