Osteopontin: A Novel Mediator of prostatic inflammation and fibrosis

项目概要/摘要 我的建议的首要目标是获得技术和专业技能，成为一个 独立调查员在领先的学术机构，并制定一项研究计划，破译 炎症诱导前列腺组织重塑和纤维化的分子机制。这将是追求 通过一个科学项目，将确定骨桥蛋白，一种促纤维化分泌的磷蛋白， 刺激前列腺炎症、纤维化和下尿路功能障碍。 我的培训集中在四个关键领域：1）小鼠泌尿功能的功能测试，2）开发 生物医学工程技术，体外研究前列腺纤维化，3）测试和进一步开发动物 研究炎症诱导的前列腺纤维化及其对泌尿功能的后果的模型，以及，4） 获得免疫调节组织重塑的基本训练。威斯康星大学麦迪逊分校和威斯康星大学奥布莱恩中心 良性泌尿外科研究提出了一个独特的环境，为拟议的研究和职业发展 活动这包括由该领域的地方和国家领导人举办的研讨会， 校园内几个研究所的活动，泌尿科的临床培训，以及具体的 免疫病理学和组织工程学的培训。 良性前列腺疾病继发的下尿路症状（LUTS）会恶化前列腺的质量 男人的年龄。男性LUTS的治疗每年花费40亿美元，并对患者造成经济负担。 我们的医疗系统最近已经确定前列腺炎症和纤维化是相关的 但这些机制对泌尿功能障碍的确切作用尚不清楚。医学疗法 靶向炎症和纤维化可以促进药物开发，并提供新的分子靶点， LUTS。基于我的初步研究，我假设炎症诱导的骨桥蛋白水平刺激了 前列腺纤维化和下尿路功能障碍（LUTD）。该假设将通过以下方式进行检验 目的： 1)检验OPN是炎症诱导的前列腺胶原积聚所必需的假设 和LUTD， 2)检验OPN诱导前列腺纤维化的假设。 该提案将提供新的检测胶原沉积，3D在体外和体内模型， 前列腺纤维化这也将解释炎症诱导的前列腺纤维化在下尿路疾病中的具体作用。 道功能障碍这将通过利用最近建立的前列腺炎症模型来实现 以及威斯康星大学麦迪逊分校独有的最先进的泌尿生理学测试。

PROJECT SUMMARY/ABSTRACT The overarching goal of my proposal is to acquire technical and professional skills to become an independent investigator at a leading academic institution and develop a research program deciphering the molecular mechanism of inflammation induced prostatic tissue remodeling and fibrosis. This will be pursued through a scientific project that will determine whether osteopontin, a pro-fibrotic secreted phosphoprotein, stimulates prostatic inflammation, fibrosis, and lower urinary tract dysfunction. My training is focused on four key areas: 1) functional testing of mouse urinary function, 2) developing biomedical engineering technologies to study prostatic fibrosis in vitro, 3) testing and further developing animal models to study inflammation-induced prostatic fibrosis and its consequences on urinary function and, 4) gaining essential training in immune-regulated tissue remodeling. UW-Madison and the UW O`Brien Center for Benign Urology Research presents a unique environment for the proposed research and career development activities. This includes seminars presented by local and national leaders of the field, career development activities of several institutes across campus, clinical training of the Department of Urology, and specific training in immunopathology and tissue engineering. Lower urinary tract symptoms (LUTS) secondary to benign prostatic diseases deteriorate the quality of life as men age. The treatment of male LUTS costs $4 billion annually and presents an economic burden on our healthcare system. It has been recently identified that prostatic inflammation and fibrosis are associated with LUTS, but the exact contribution of these mechanism to urinary dysfunction is unknown. Medical therapies targeting inflammation and fibrosis could enhance drug development and provide novel molecular targets for LUTS. Based on my preliminary studies, I hypothesize that inflammation-induced osteopontin levels stimulate prostatic fibrosis and lower urinary tract dysfunction (LUTD). The hypothesis will be tested by the following aims: 1) Test the hypothesis that OPN is required for inflammation-induced prostatic collagen accumulation and LUTD, 2) Test the hypothesis that OPN induces prostatic fibrosis. The proposal will provide novel detection of collagen deposition, 3D in vitro and in vivo models of prostatic fibrosis. It will also decipher the specific role of inflammation-induced prostatic fibrosis in lower urinary tract dysfunction. This will be achieved by capitalizing on recently established prostatic inflammation models and state-of-the-art urinary physiological tests uniquely available at the UW-Madison.