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/慢性盆腔疼痛综合征 (CP/CPPS) 影响多达 16% 的男性，并带来巨大的生活质量和经济后果。目前，缺乏治疗方案来控制通常伴随这种疾病的疼痛和排尿症状。开发和部署能够概括人类 CP/CPPS 关键病理特征的小动物模型，可以极大地促进有效疗法的开发。我们最近开发了一种转基因小鼠 CP/CPPS 模型，该模型基于前列腺中促炎细胞因子 IL-1ss 的诱导表达。这些小鼠患上慢性前列腺炎，可通过在饮用水中施用多西环素来调节，并显示出明显的炎性疼痛和排尿模式变化的证据。这里提出的工作的总体目标是剖析炎症性疼痛和排尿症状的分子基础，为治疗这种疾病的新治疗策略提供信息。我们建议确定两个瞬时受体电位通道 (TRP) TRPA1 和 TRPV1 在介导前列腺炎症的生理反应中所发挥的作用。 TRPA1 和 TRPV1 均被炎症环境中产生的物质激活，并介导其他组织的炎症症状。我们将从多学科的角度来解决这个问题，汇集专门开发小鼠前列腺疾病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。拟议工作的成功完成将确定 TRPA1 和/或 TRPV1 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例来剖析任何基因在该疾病的病因或进展中的作用。