Role of TRPA1 & TRPV1 in pain and voiding symptoms in a new mouse CP/CPPS model

描述(申请人提供)：慢性前列腺炎/慢性盆腔疼痛综合征(CP/CPPS)影响多达16%的男性，并具有巨大的生活质量和经济后果。目前，缺乏治疗选择来管理疼痛和排尿症状，通常伴随这种疾病。通过开发和部署总结人类CP/CPPS关键病理特征的小动物模型，可以极大地促进有效治疗的开发。我们最近开发了一种转基因小鼠CP/CPPS模型，该模型基于促炎细胞因子IL-1SS在前列腺癌中的诱导表达。这些小鼠患上慢性前列腺炎，可以通过在饮用水中注射多西环素来调节，并显示出明显的炎性疼痛和排尿模式改变的证据。这项工作的首要目标是剖析炎性疼痛和排尿症状的分子基础，为治疗这种疾病提供新的治疗策略。我们建议确定两个瞬时受体潜在通道(TRP)，TRPA1和TRPV1，在调节前列腺炎症的生理反应中所起的作用。TRPA1和TRPV1都被炎症环境中产生的介质激活，并在其他组织中介导炎症症状。我们将从多学科的角度处理这个问题，汇集专门研究前列腺癌小鼠模型的小鼠发育遗传学家和专门研究Trp通道功能的小鼠感觉神经生理学家的专业知识。这项拟议工作的成功完成将确定TRPA1和/或TRPV1是否为治疗人类CP/CPPS症状的可行治疗靶点，并将提供一个新的范例来剖析任何基因在这种疾病的病因或进展中的作用。

DESCRIPTION (provided by applicant): Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) affects as many as 16% of men and has enormous quality of life and economic consequences. Currently, there is a dearth of treatment options to manage the pain and voiding symptoms that typically accompany this disease. The development of effective therapies can be greatly facilitated by the development and deployment of small animal models that recapitulate key pathological features of human CP/CPPS. We have recently developed a transgenic mouse CP/CPPS model based on inducible expression of the pro- inflammatory cytokine IL-1ss in the prostate gland. These mice develop chronic prostatitis that can be regulated by administration of Doxycycline in the drinking water, and show clear evidence of inflammatory pain and changes in micturition pattern. The overarching goal of the work proposed here is to dissect the molecular basis of the inflammatory pain and voiding symptoms to inform new therapeutic strategies to treat this disease. We propose to determine the roles played by two Transient Receptor Potential channels (TRP), TRPA1 and TRPV1, in mediating physiological responses to prostatic inflammation. Both TRPA1 and TRPV1 are activated by agents produced in inflammatory environments, and mediate inflammatory symptoms in other tissues. We will approach this problem from a multidisciplinary perspective, bringing together the expertise of a mouse developmental geneticist who specializes in developing mouse models of prostate disease, and a mouse sensory neurophysiologist who specializes in the function of TRP channels. The successful completion of the proposed work will determine whether TRPA1 and/or TRPV1 are viable therapeutic targets to treat human CP/CPPS symptoms, and will provide a new paradigm to dissect the role of any gene in the etiology or progression of this disease.