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

尿路功能障碍发展过程中纤维化的细胞和分子介质

• 批准号: 9921105
• 负责人: WILLIAM A RICKE
• 金额: $ 120万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-24 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921105
• 关键词: Adverse effects; Affect; Animals; Benign; Biomedical Research; Bladder; Boston; Breeding; Cell Lineage; Cells; Cheese; Clinical; Collaborations; Collagen; Communication; Communities; Computer software; Consensus; Consequentialism; Data; Databases; Development; Diagnosis; Educational process of instructing; Elderly; Environment; Estrogen Receptor alpha; Etiology; FDA approved; Fibroblasts; Fibrosis; Financial Support; Fostering; Freezing; Frozen Semen; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; Genetic Transcription; Goals; Health Care Costs; Histologic; Human; Image; Impairment; Inflammation; Inflammatory; Infrastructure; Insignia; Institution; Interleukin-13; Interleukin-4; Investigation; Lead; Leadership; Learning; Lobster; Lower urinary tract; Maps; Mediator of activation protein; Medical; Metadata; Methods; Molecular; Molecular Target; Mouse Strains; Mus; Myofibroblast; Pathway interactions; Physicians; Physiology; Pre-Clinical Model; Process; Proliferating; Prostate; Prostatic; Prostatic Tissue; Protocols documentation; Publications; Quality of life; Reproducibility; Research; Research Personnel; Research Project Grants; Resistance; Resources; SECTM1 gene; SRD5A2 gene; Sampling; Scientific Advances and Accomplishments; Scientist; Smooth Muscle; Solid; Source; Specimen; Steroids; Stream; Stromal Cells; Sum; Symptoms; Testing; Testosterone 5-alpha-Reductase; Therapeutic; Tissues; Training; Ultrasonography; Urethra; Urinary tract; Urination; Urine; Urology; Vision; Voice; Work; analytical method; biobank; connective tissue growth factor; contrast enhanced; data sharing; design; experience; imaging modality; improved; in vivo; inhibitor/antagonist; innovation; lower urinary tract symptoms; male; member; men; mouse model; novel therapeutics; pre-clinical; preclinical study; programs; radiological imaging; single-cell RNA sequencing; synergism; tissue resource; tool; undergraduate research; undergraduate student; urinary; urologic; web site

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.

项目概要 - 总体 前列腺相关下尿路症状 (LUTS) 的医学治疗尚未取得相应进展 现有的药物疗法可以改善 LUTS，但这些效果的稳健性微乎其微。 并非所有男性都对现有疗法有反应，有些人会出现不良反应，需要停止治疗 治疗，并且大多数人在最初缓解后症状会逐渐恶化。 机制驱动前列腺相关 LUTS 的发展和进展 O’Brien 的总体目标。 良性泌尿外科研究中心旨在确定导致下尿路功能障碍和 该中心的首要假设是纤维化是男性 LUTS 的一个原因。 与良性前列腺肥大和平滑肌功能障碍相比，前列腺纤维化仍然没有针对性 通过现有的疗法，以促进对前列腺的科学认识和医疗管理。 纤维化，有必要：（1）识别纤维化的细胞和分子介质并进行治疗- 使用临床标本的易感途径，（2）开发和验证前列腺的临床前小鼠模型 纤维化和排尿功能精细评估策略，（3）在这些临床前测试新疗法 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将推进另外两个目标。 泌尿学研究界：(1) 开发并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 该中心将吸引年轻的基础科学家和医师科学家进入良性泌尿外科研究领域。 艺术分子和组织学方法可视化和表征一系列人类和动物的纤维化 前列腺组织并检查前列腺纤维化如何发生、进展以及对治疗的反应。 与奥布莱恩中心的互动核心、威斯康星大学奥布莱恩中心网站的互动和参与，以及 GUDMAP 将加速数据、软件、方法和组织资源向更大范围的传播 该中心的领导力和经验将有助于促进生物医学界的发展。 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 更大的愿景是奥布莱恩中心将成为沟通、协作和协调的中心。 为了实现这一目标，泌尿学研究界需要理念、研究、资源、培训和统一的声音。 威斯康星大学奥布莱恩中心及其附属机构的愿景是，这些中心必须超越其各个部分的总和。 通过利用现有中心资产和关系、开展严格的 调查研究，培育教学，锐意创新，凭借雄厚的财力。 在华盛顿大学及其附属机构的支持和“认可”下，Core A 将引领奥布莱恩中心的这一愿景。