Mast cells in male pelvic pain and lower urinary tract 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)是一种衰弱的内科疾病，以排尿困难和会阴、睾丸、阴茎和耻骨上区域疼痛为特征。在美国，前列腺炎每年影响近200万人，90%的病例被诊断为慢性前列腺炎。建立该综合征的始发因素尚不清楚。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(PAR2)在实验性自身免疫性前列腺炎(EAP)动物模型的疾病发病机制中发挥着重要作用。PAR2是唯一已知的肥大细胞类胰蛋白酶的同源受体，在我们的研究中观察到在CP/CPPS患者的前列腺分泌物中显著升高的关键蛋白水解酶。在前列腺，骨盆疼痛的发展需要肥大细胞类胰蛋白酶-PAR2轴，我们发现类胰蛋白酶-PAR2的激活导致背根神经节(DRG)神经元的敏化。PAR2基因缺陷的小鼠表现出盆腔疼痛减轻，并且没有DRG敏感性。本项目建议的研究将建立在这些先前观察的基础上，以确定PAR2介导的外周敏化的潜在机制，并研究外周机制如何影响慢性盆腔疼痛的维持。此外，我们建议定义类胰蛋白酶-PAR2轴在EAP中与纤维化和LUTS相关的新角色。使用EAP动物模型，我们观察到与PAR2信号相关的纤维化标志物的增加和尿路功能障碍的存在。这些结果提示类胰蛋白酶-PAR2轴在调节EAP的尿路症状中起着关键作用。因此，我们假设肥大细胞类胰蛋白酶-PAR2信号介导了盆腔疼痛的发生和维持，并促进了导致LUTS发生的前列腺纤维化的机制。最后，我们提出了一个翻译目标，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减少肥大细胞类胰蛋白酶，并影响慢性盆腔疼痛和下尿路感染。这些研究有可能对我们理解CP/CPPS的发病机制产生重大影响，并为患者开发有针对性的治疗方法。

 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.