Mast cells in male pelvic pain and lower urinary tract dysfunction

 描述（由申请人提供）：慢性前列腺炎/慢性骨盆疼痛综合征（CP/CPPS）是一种使人衰弱的疾病，其特征为排尿困难和会阴、睾丸、阴茎和耻骨上区域疼痛。在美国，前列腺炎每年影响近200万人，其中90%的病例接受CPPS的诊断。建立该综合征的起始因素尚不清楚。在我们以前的研究中，我们已经确定了一个关键的蛋白酶-肥大细胞类胰蛋白酶及其同源受体蛋白酶激活受体2（PAR 2）作为重要的球员在疾病的发病机制中的实验性自身免疫性前列腺炎（EAP）的动物模型。PAR 2是肥大细胞类胰蛋白酶的唯一已知同源受体，在我们的研究中观察到的关键蛋白酶在CP/CPPS患者的前列腺分泌物中显著升高。在前列腺，盆腔疼痛的发展需要肥大细胞类胰蛋白酶-PAR 2轴，我们表明类胰蛋白酶-PAR 2激活导致背根神经节（DRG）的神经元敏化。PAR 2缺陷小鼠表现出减弱的骨盆疼痛和缺乏DRG致敏。本项目中提出的研究将建立在这些先前的观察结果的基础上，以确定PAR 2介导的外周致敏的机制，并研究外周机制如何维持慢性盆腔疼痛。此外，我们建议定义一个新的作用，类胰蛋白酶-PAR 2轴在EAP方面的纤维化和LUTS。使用EAP动物模型，我们观察到纤维化标志物的增加和与PAR 2信号传导相关的泌尿功能障碍的存在。这些结果表明类胰蛋白酶-PAR 2轴在介导EAP患者的泌尿系统症状中起关键作用。因此，我们假设肥大细胞类胰蛋白酶-PAR 2信号介导盆腔疼痛的发生和维持，并促进前列腺纤维化机制，导致LUTS的发展。最后，我们提出了一个转化目标，我们将在人类患者中进行概念验证试点研究，以确定治疗干预是否能够降低肥大细胞类胰蛋白酶并影响慢性盆腔疼痛和LUTS。这些研究有可能对我们理解CP/CPPS发病机制产生重大影响，并为患者开发靶向治疗。

 DESCRIPTION (provided by applicant): Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) is a debilitating medical condition characterized by dysuria and pain in the perineum, testes, penis and suprapubic region. Prostatitis affects nearly 2 million people annually in the United States with 90% of all cases receiving a diagnosis of CPPS. The initiating factors that establish the syndrome are unknown. In our previous studies we have identified a key protease - mast cell tryptase and its cognate receptor protease activated receptor-2 (PAR2) as important players in disease pathogenesis in the experimental autoimmune prostatitis (EAP) animal model. PAR2 is the only known cognate receptor for mast cell tryptase, the key protease that was observed in our studies to be significantly elevated in prostatic secretions of CP/CPPS patients. In the prostate, the development of pelvic pain requires the mast cell tryptase-PAR2 axis and we show that tryptase-PAR2 activation leads to sensitization of neurons at the dorsal root ganglia (DRG). PAR2 deficient mice showed attenuated pelvic pain and an absence of DRG sensitization. The studies proposed in this project will build on these previous observations to identify the mechanism underlying PAR2-mediated peripheral sensitization and examine how peripheral mechanisms feed into the maintenance of chronic pelvic pain. Furthermore, we propose to define a novel role for the tryptase-PAR2 axis in EAP with regard to fibrosis and LUTS. Using the EAP animal model we observed increased markers of fibrosis and the presence of urinary dysfunction that were linked to PAR2 signaling. These results suggest a critical role for the tryptase- PAR2 axis in mediating urinary symptoms in EAP. We therefore hypothesize that mast cell tryptase-PAR2 signaling mediates the development and maintenance of pelvic pain and promotes mechanisms of prostate fibrosis that result in the development of LUTS. Finally we propose a translational aim where we will perform proof of concept pilot studies in human patients to identify whether therapeutic intervention is capable of reducing mast cell tryptase and influencing chronic pelvic pain and LUTS. These studies have the potential to have a significant impact on our understanding of CP/CPPS pathogenesis and to develop targeted therapies for patients.