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

TRPA1 的作用

• 批准号: 8627453
• 负责人: CHARLES J. BIEBERICH
• 金额: $ 29.66万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-27 至 2015-09-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627453
• 关键词: Affect; Animal Model; Chronic Prostatitis; Development; Disease; Disease Progression; Doxycycline; Economics; Environment; Etiology; Foundations; Functional disorder; Genes; Goals; Human; Inflammation; Inflammatory; Ion Channel; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Outcome; Pain; Pain management; Pattern; Physiological; Play; Prostate; Prostatic; Prostatic Diseases; Proteins; Quality of life; Recurrence; Role; Sensory; Symptoms; TRPA1 Channel; TRPV1 gene; Testing; Tissues; Transgenic Mice; Urination; Work; base; chronic pelvic pain; cytokine; design; drinking water; effective therapy; efficacy testing; experience; human disease; in vivo; inflammatory pain; men; mouse model; multidisciplinary; novel therapeutics; pre-clinical; public health relevance; receptor; response; therapeutic target

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.

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）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通常伴随这种疾病的疼痛和排尿症状。通过开发和部署小动物模型可以大大促进有效疗法的开发，这些模型概括了人类CP/CPPS的关键病理特征。我们最近开发了一种转基因小鼠CP/CPPS模型，该模型基于前列腺中促炎细胞因子IL-1 β的诱导表达。这些小鼠发生慢性前列腺炎，可以通过在饮用水中给予强力霉素来调节，并显示出明显的炎性疼痛和排尿模式变化的证据。本文提出的工作的总体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电位通道（TRP），TRPA 1和TRPV 1，在介导前列腺炎症的生理反应中发挥的作用。TRPA 1和TRPV 1都被炎症环境中产生的试剂激活，并介导其他组织中的炎症症状。我们将从多学科的角度来解决这个问题，汇集了专门从事开发前列腺疾病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。这项工作的成功完成将确定TRPA 1和/或TRPV 1是否是治疗人类CP/CPPS症状的可行治疗靶点，并将提供一个新的范式来剖析任何基因在这种疾病的病因或进展中的作用。