Tryptase - PAR2 axis involved in urinary voiding dysfunction

类胰蛋白酶 - PAR2 轴参与排尿功能障碍

• 批准号: 8836158
• 负责人: Kenny M Roman
• 金额: $ 5.36万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836158
• 关键词: Address; Affect; Autoimmune Process; Behavioral Assay; Benign Prostatic Hypertrophy; Bladder; Bladder Dysfunction; Chronic; Chronic Prostatitis; Clinical; Cohort Studies; Data; Development; Disease; Elasticity; Erectile dysfunction; Etiology; Event; Fibrosis; Figs - dietary; Frequencies; Functional disorder; Funding; Immunohistochemistry; Increased frequency of micturition; Inflammation; Label; Laboratories; Lead; Link; MAPK3 gene; Measures; Mediating; Mediator of activation protein; Mental Health; Methods; Modeling; Mus; Obstruction; Organ; PAR-2 Receptor; Pain; Pathogenesis; Patients; Pattern; Pelvic Pain; Peptide Hydrolases; Phosphorylation; Population; Prostate; Prostatic; Publishing; Quality of life; Reporting; Research Project Grants; Research Proposals; Role; Sensory; Signal Transduction; Smooth Muscle Actin Staining Method; Spinal Ganglia; Symptoms; Therapeutic; Tryptase; United States National Institutes of Health; Urethra; activity marker; base; chronic pain; chronic pelvic pain; cohort; effective therapy; experience; health related quality of life; improved; in vivo; lower urinary tract symptoms; male; mast cell; men; mouse model; neurotransmitter release; new therapeutic target; novel; prostatitis; public health relevance; research study; response; urinary

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.

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）是一种多症状的临床问题，涉及持续3个月以上的疼痛，并导致排尿功能障碍。由于对其病因和发病机制的了解不完全，治疗选择很少。在我们实验室进行的研究表明，肥大细胞类胰蛋白酶激活蛋白酶激活受体2（PAR 2）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是一种模拟CP/CPPS的小鼠模型。然而，迄今为止，还没有探讨型蛋白酶-PAR 2轴作为CP/CPPS患者报告的泌尿系统症状的潜在介导因素。拟议的研究项目旨在研究CP/CPPS小鼠模型中类胰蛋白酶-PAR 2轴与排尿功能障碍之间的联系。本研究提案中提出的初步研究显示，PAR 2可能参与排尿功能障碍。简而言之，数据显示患有EAP的小鼠具有增加的排尿频率。此外，患有EAP的小鼠的前列腺具有增加的α-平滑肌肌动蛋白（α-SMA）（纤维化标志物）的表达。相比之下，用EAP敲低PAR 2（KO）不显示排尿频率的变化，并且前列腺不显示α-SMA表达的变化。此外，我们报告说，过敏的背根神经节由于PAR 2激活发生在EAP小鼠，这表明前列腺和膀胱之间的跨器官敏化可能会导致泌尿系统症状。基于初步数据，我们假设肥大细胞类胰蛋白酶-PAR 2轴是前列腺纤维化和致敏的新调节因子，导致膀胱功能障碍。拟议的研究项目将使用以下具体目标来解决该假设：1）确定类胰蛋白酶激活前列腺中PAR 2对膀胱功能障碍的作用，以及2）确定类胰蛋白酶-PAR 2轴对前列腺和膀胱共享的DRG中跨器官致敏的影响。总之，这些目标的结果将阐明我们对CP/CPPS患者泌尿系统症状诱导的理解，并确定治疗排尿功能障碍的新治疗靶点。