Cellular and molecular mediators of fibrosis in the development of urinary tract dysfunction

项目概要-总体 前列腺相关下尿路症状（LUTS）的药物治疗没有相应的进展， 出现在几十年前。现有的医学疗法改善了LUTS，但这些效果的稳健性是微不足道的。 并不是所有的男性都对现有的治疗有反应，有些人会产生不良反应，需要停止治疗。 治疗，并且大多数经历根据初始缓解的症状的进行性恶化。多 机制驱动前列腺相关LUTS的发展和进展。奥布莱恩的首要目标是 良性泌尿学研究中心是为了确定导致下尿路功能障碍的机制， 前列腺相关LUTS。该中心的首要假设是纤维化是男性LUTS的原因。在 与良性前列腺肥大和平滑肌功能障碍相反，前列腺纤维化仍然是非靶向的 现有的疗法。为了提高对前列腺疾病的科学认识和医疗管理水平， 为了治疗纤维化，有必要：（1）鉴定纤维化的细胞和分子介导物和治疗- 使用临床标本的敏感途径，（2）开发和验证前列腺临床前小鼠模型 纤维化和排尿功能的颗粒评估策略，（3）在这些临床前试验中测试新疗法 长期目标是治疗男性纤维化的模型，以及（4）开发新的非侵入性放射成像 长期目标是诊断男性前列腺纤维化。另外两个目标将推动 泌尿外科研究界：（1）开发和公开传播资源，以提高研究效率， 可重复性和严谨性，以及（2）培养优秀的教育丰富计划，以吸引和留住 年轻的基础科学家和医生科学家进入良性泌尿外科研究领域。该中心将适用国家的 本发明涉及一种用于在一系列人和动物中可视化和表征纤维化的分子和组织学方法 前列腺组织，并检查前列腺纤维化如何发展，进展和对治疗的反应。 与奥布莱恩中心互动核心、华盛顿大学奥布莱恩中心网站的互动和参与， GUDMAP将加速数据、软件、方法和组织资源的传播， 生物医学社区中心内的领导和经验将有助于促进 中心项目、生物医学研究核心和其他中心（U 54、P20、K12）之间的互动， 沟通、协作和协调。更大的愿景是，奥布莱恩中心将成为一个病灶， 想法，研究，资源，培训，以及泌尿外科研究界的统一声音。实现这一 为了实现这一愿景，各中心必须超越其各部分的总和。华盛顿大学奥布莱恩中心及其附属机构将 通过利用现有的中心资产和关系， 研究，促进教学和学习，并通过积极追求创新。凭借坚实的财务 支持和“买进”从华盛顿大学及其附属机构，核心A将导致这一愿景的奥布莱恩中心。

PROJECT SUMMARY- OVERALL No consequential advances in medical treatment of prostate-related lower urinary tract symptoms (LUTS) have emerged in decades. Existing medical therapies improve LUTS but robustness of these effects are marginal. Not all men respond to existing therapies, some respond with adverse effects requiring discontinuation of therapy, and most experience a progressive worsening of symptoms pursuant to initial relief. Multiple mechanisms drive development and progression of prostate-related LUTS. The overarching goal of the O’Brien Center for Benign Urology Research is to identify mechanisms that result in lower urinary tract dysfunction and prostate-related LUTS. The overarching hypothesis of the center is that fibrosis is a cause of male LUTS. In contrast to benign prostatic enlargement and smooth muscle dysfunction, prostatic fibrosis remains untargeted by existing therapies. In order to advance the scientific understanding and medical management of prostatic fibrosis, it will be necessary to: (1) identify cellular and molecular mediators of fibrosis and therapeutically- susceptible pathways using clinical specimens, (2) develop and validate preclinical mouse models of prostatic fibrosis and strategies for granular assessment of voiding function, (3) test new therapies in these preclinical models with the long term goal of treating fibrosis in men, and (4) develop new non-invasive radiologic imaging strategies with the long-term goal of diagnosing prostatic fibrosis in men. Two additional goals will advance the urologic research community: (1) develop and publicly disseminate resources to increase research efficiency, reproducibility, and rigor, and (2) cultivate an outstanding educational enrichment program to attract and retain young basic- and physician-scientists into the benign urologic research field. The Center will apply state of the art molecular and histological methods to visualize and characterize fibrosis in a range of human and animal prostatic tissues and examine how prostatic fibrosis develops, progresses, and responds to treatment. Interactions and engagement with the O’Brien Centers’ Interaction Core, the UW O’Brien Centers Website, and GUDMAP will accelerate the dissemination of data, software, methods, and tissue resources to the greater biomedical community. The leadership and experience within the Center will allow for the promotion of interactions among Center Projects, the Biomedical Research Core, and other Centers (U54, P20, K12) through communication, collaboration, and coordination. The larger vision is that O’Brien Centers will be a nidus for ideas, research, resources, training, and a unified voice across the urologic research community. To realize this vision, the Centers must become more than the sum of their parts. The UW O’Brien Center and its affiliates will contribute to this synergism by leveraging existing Center assets and relationships, conducting rigorous investigation, fostering teaching and learning, and through vigorous pursuit of innovation. With the solid financial support and “buy-in” from UW and its affiliates, Core A will lead this vision for this O’Brien Center.