Tryptase - PAR2 axis involved in urinary voiding dysfunction

描述(申请人提供)：慢性前列腺炎/慢性盆腔疼痛综合征(CP/CPPS)是一种多症状的临床问题，疼痛持续3个月以上，并导致排尿功能障碍。由于对其病因和发病机制的不完全了解，治疗方案很少。我们实验室进行的研究表明，肥大细胞类胰蛋白酶激活的蛋白酶激活受体2(PAR2)与实验性自身免疫性前列腺炎(EAP)小鼠的慢性盆腔疼痛直接相关，EAP是一种模仿CP/CPPS的小鼠模型。然而，到目前为止，类型酶-PAR2轴还没有被报道为CP/CPPS患者尿路症状的潜在介体。这项拟议的研究项目试图在CP/CPPS小鼠模型中调查类胰蛋白酶-PAR2轴与尿排尿功能障碍之间的联系。这项研究提案中提出的初步研究表明，PAR2可能参与了排尿功能障碍。简而言之，数据显示患有EAP的小鼠尿频增加。此外，患有EAP的小鼠的前列腺组织中纤维化标志物--α-SMA的表达增加。相比之下，PAR2基因敲除(KO)和EAP对尿频没有影响，前列腺组织中a-SMA的表达也没有变化。此外，我们还报道了由PAR2激活引起的背根节敏化在EAP小鼠中发生，提示前列腺和膀胱之间的跨器官敏化可能导致泌尿症状。根据初步数据，我们假设肥大细胞类胰蛋白酶-PAR2轴是导致膀胱功能障碍的前列腺纤维化和敏化的新调节因子。这项拟议的研究项目将利用以下具体目标解决这一假说：1)确定PAR2在前列腺中的类胰蛋白酶激活在膀胱功能障碍中的作用；2)确定类胰酶-PAR2轴在前列腺和膀胱共享的DRG跨器官敏化中的作用。总体而言，这些目标的结果将澄清我们对CP/CPPS患者尿路症状诱导的理解，并确定治疗尿路排尿功能障碍的新靶点。

DESCRIPTION (provided by applicant): Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a multi-symptomatic clinical problem that involves pain lasting more than 3 months and leads to urinary voiding dysfunction. There are few therapeutic options due to an incomplete understanding of its etiology and pathogenesis. Studies conducted in our laboratory revealed that mast-cell tryptase activation of protease-activated receptor 2 (PAR2) is directly linked to chronic pelvic pain in mice with experimental autoimmune prostatitis (EAP), a mouse model that mimics aspects of CP/CPPS. However, to date, the typtase-PAR2 axis has not been explored as a potential mediator of urinary symptoms reported by CP/CPPS patients. The proposed research project seeks to investigate the link between tryptase-PAR2 axis and urinary voiding dysfunction in a mouse model of CP/CPPS. Preliminary studies presented in this research proposal revealed that PAR2 may be involved in urinary voiding dysfunction. Briefly, data showed that mice with EAP have increased urinary frequency. Also, the prostate of mice with EAP have increased expression of alpha-smooth muscle actin (a-SMA), a fibrosis marker. In contrast, PAR2 knockdown (KO) with EAP do not show changes to urinary frequency and the prostate showed no change in a-SMA expression. In addition, we report that sensitization of dorsal root ganglia due to PAR2 activation occurs in mice with EAP, suggesting that cross-organ sensitization between the prostate and bladder may lead to urinary symptoms. Based on the preliminary data we hypothesize that the mast cell tryptase-PAR2 axis is a novel regulator of prostate fibrosis and sensitization that leads to bladder dysfunction. The proposed research project will address the hypothesis using the following specific aims: 1) Determine the role of tryptase activation of PAR2 in the prostate on bladder dysfunction and 2) determine the effect of the tryptase-PAR2 axis on cross-organ sensitization in DRG shared by the prostate and bladder. Overall, the results from these aims will elucidate our understanding of the induction of urinary symptoms in CP/CPPS patients and identify a novel therapeutic target for treating urinary voiding dysfunction.