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

项目总结--总体 前列腺相关下尿路症状(LUT)的医学治疗没有相应的进展 在几十年里出现了。现有的医学疗法可以改善下尿路感染，但这些效果的稳健性是微乎其微的。 并不是所有的男性都对现有的治疗方法有反应，有些人的反应是副作用，需要停用 治疗，大多数人经历了症状的逐渐恶化，根据最初的缓解。多重 机制推动了前列腺癌的发生和发展。奥布莱恩的首要目标 良性尿路研究中心是为了确定导致下尿路功能障碍的机制和 与前列腺相关的下尿路结节。该中心的首要假设是，纤维化是男性LUTS的原因之一。在……里面 与良性前列腺增大和平滑肌功能障碍相比，前列腺纤维化仍然没有靶点。 通过现有的治疗方法。为提高对前列腺癌的科学认识和医学管理水平 对于纤维化，有必要：(1)确定纤维化的细胞和分子介质，并在治疗上- 使用临床标本的易感途径，(2)建立和验证临床前前列腺癌小鼠模型 纤维化和排尿功能的颗粒评估策略，(3)在这些临床前测试新的治疗方法 以治疗男性纤维化为长期目标的模型，以及(4)开发新的非侵入性放射成像 以诊断男性前列腺纤维化为长期目标的策略。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)培养优秀的教育充实计划，以吸引和留住 年轻的基础和内科科学家进入良性泌尿外科研究领域。该中心将应用 ART分子和组织学方法在一系列人和动物中可视化和表征纤维化 并检查前列腺纤维化的发展、进展和对治疗的反应。 与奥布莱恩中心的互动核心、密歇根大学奥布莱恩中心网站以及 GUDMAP将加快数据、软件、方法和组织资源的传播 生物医学社区。该中心的领导力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(U54、P20、K12)之间的互动通过 沟通、协作和协调。更大的愿景是，奥布莱恩中心将成为 想法、研究、资源、培训，以及整个泌尿科研究社区的统一声音。要认识到这一点 展望未来，中心必须不仅仅是它们各部分的总和。威斯康星大学奥布莱恩中心及其附属机构将 通过利用现有中心资产和关系、进行严格的 通过调查，培养教与学，并通过大力追求创新。凭借雄厚的财务实力 在UW及其附属公司的支持和“买入”下，Core A将领导这个奥布莱恩中心的愿景。

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.