Mast cells in male pelvic pain and lower urinary tract dysfunction

肥大细胞在男性盆腔疼痛和下尿路功能障碍中的作用

• 批准号: 9303340
• 负责人: PRAVEEN THUMBIKAT
• 金额: $ 34.76万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303340
• 关键词: ATP Receptors; Acute; Address; Affect; American; Animal Model; Anogenital region; Attenuated; Autoimmune Process; Benign Prostatic Hypertrophy; Bladder; Brain-Derived Neurotrophic Factor; CCL3 gene; CXCL12 gene; Categories; Cell physiology; Chronic Kidney Failure; Chronic Prostatitis; Chymase; Clinical; Collagen; County; Development; Diagnosis; Disease; Dysuria; Elasticity; Evaluation; Fibrosis; Frequencies; Functional disorder; Hamman-Rich syndrome; Human; Immune; Inflammation; Interleukin-7; Kidney; Link; Lower urinary tract; Maintenance; Mediating; Medical; Methods; Microglia; Morbidity - disease rate; Mus; Neurons; PAR-2 Receptor; Pain; Pathogenesis; Patients; Pelvic Pain; Peptide Hydrolases; Peripheral; Physicians; Pilot Projects; Play; Prostate; Prostatic; Prostatism; Proteinase-Activated Receptors; Quality of life; Resolution; Role; STAT6 gene; Sacral spinal cord structure; Signal Transduction; Smooth Muscle Actin Staining Method; Source; Spinal Ganglia; Symptoms; Syndrome; TRPV1 gene; Testing; Testis; Therapeutic Intervention; Tissues; Tryptase; United States; Urethra; Urethral Obstruction; Urinary Retention; chemokine; chronic pain; chronic pelvic pain; cytokine; feeding; lower urinary tract symptoms; male; male health; mast cell; member; men; molecular marker; novel; penis; prostatitis; public health relevance; receptor; targeted treatment; urinary

 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.

 描述（由应用提供）：慢性前列腺炎/慢性骨盆疼痛综合征（CP/CPP）是一种使人衰弱的疾病，其特征是阴部，睾丸，阴茎和肩apo骨区域的缺乏症和疼痛。在美国，前列腺炎每年影响近200万人，其中90％的病例接受了CPP的诊断。建立综合征的起始因素尚不清楚。在我们先前的研究中，我们已经确定了一个关键的蛋白酶 - 肥大细胞胰蛋白酶及其同源受体蛋白酶活化受体-2（PAR2）是实验性自身免疫前列腺炎（EAP）动物模型中疾病发病机理的重要参与者。 PAR2是肥大细胞胰蛋白酶的唯一已知的同源受体，这是我们研究中观察到的关键蛋白酶在CP/CPP患者的前列腺分泌中显着升高。在前列腺中，骨盆疼痛的发育需要肥大细胞胰蛋白酶-Par2轴，我们表明胰蛋白酶-Par2激活会导致背根神经节（DRG）的神经元敏感性。 PAR2缺乏的小鼠显示骨盆疼痛减弱和缺乏DRG敏感性。该项目中提出的研究将基于这些先前的观察结果，以识别PAR2介导的外围感觉的基础机制，并研究外围机制如何进食慢性骨盆疼痛的维持。此外，我们建议在EAP中在纤维化和LUTS方面定义胰酶-par2轴的新作用。使用EAP动物模型，我们观察到与PAR2信号有关的纤维化标记和尿功能障碍的存在。这些结果表明，胰酶-PAR2轴在EAP中介导尿症状中起着至关重要的作用。因此，我们假设肥大细胞胰蛋白酶-PAR2信号传导介导骨盆疼痛的发展和维持，并促进前列腺纤维化的机制，从而导致LUTS的发展。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试验验证，以确定治疗干预是否能够减少肥大细胞胰蛋白酶并影响慢性骨盆疼痛和LUTS。这些研究有可能对我们对CP/CPP发病机理的理解产生重大影响，并为患者开发针对性的疗法。