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

基本信息

批准号：
10700913
负责人：
WILLIAM A RICKE
金额：
$ 119.68万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
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/10700913
关键词：
Acceleration Adverse effects Affect Animals Benign Biomedical Research Bladder Boston Breeding Cell Lineage Cells Cheese Clinical Collaborations Collagen Communication Communities Computer software Consensus Data Databases Development Diagnosis Education 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 Medical Mentored Clinical Scientist Development Program Metadata Methods Molecular Molecular Target Mouse Strains Mus Myofibroblast Pathway interactions Physicians Physiology Pre-Clinical Model Predisposition Process Proliferating Prostate Prostatic Prostatic Tissue Protocols documentation Publications Quality of life Reproducibility Research Research Personnel Research Project Grants Resistance Resources 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 Urethra Urinary tract Urination Urine Urology Vision Visualization Voice Work analytical method biobank connective tissue growth factor contrast enhanced data dissemination data sharing design experience imaging modality improved in vivo inhibitor innovation lower urinary tract symptoms male member men mouse model novel therapeutics older men pre-clinical preclinical study programs radiological imaging searchable database single-cell RNA sequencing synergism tissue resource tool ultrasound undergraduate research experience undergraduate student urinary urologic web site

项目摘要

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。泌尿外科研究界：(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）培养出色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。

项目成果

期刊论文数量（103）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Micturition defects and altered bladder function in the klotho mutant mouse model of aging.

klotho 突变小鼠衰老模型中的排尿缺陷和膀胱功能改变。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Bartolone, Sarah N;Ward, Elijah P;Wang, Zunyi;Zwaans, Bernadette Mm;Chancellor, Michael B;Bjorling, Dale E;Lamb, Laura E
通讯作者：
Lamb, Laura E

A mechanism linking perinatal 2,3,7,8 tetrachlorodibenzo-p-dioxin exposure to lower urinary tract dysfunction in adulthood.

围产期 2,3,7,8 四氯二苯并-对二恶英暴露与成年期下尿路功能障碍之间存在联系的机制。

DOI：
发表时间：
2021
期刊：
影响因子：
4.3
作者：
Turco, Anne E;Oakes, Steven R;Keil Stietz, Kimberly P;Dunham, Cheryl L;Joseph, Diya B;Chathurvedula, Thrishna S;Girardi, Nicholas M;Schneider, Andrew J;Gawdzik, Joseph;Sheftel, Celeste M;Wang, Peiqing;Wang, Zunyi;Bjorling, Dale E;Ricke, Willi
通讯作者：
Ricke, Willi

Complementary proteome and glycoproteome access revealed through comparative analysis of reversed phase and porous graphitic carbon chromatography.

通过反相和多孔石墨碳色谱的比较分析揭示了互补的蛋白质组和糖蛋白质组。

DOI：
发表时间：
2022-07
期刊：
影响因子：
4.3
作者：
Delafield, Daniel G;Miles, Hannah N;Liu, Yuan;Ricke, William A;Li, Lingjun
通讯作者：
Li, Lingjun

Inhibition of the CXCL12/CXCR4 axis prevents periurethral collagen accumulation and lower urinary tract dysfunction in vivo.

抑制 CXCL12/CXCR4 轴可防止尿道周围胶原蛋白积累和体内下尿路功能障碍。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Macoska, Jill A;Wang, Zunyi;Virta, Johanna;Zacharias, Nicholas;Bjorling, Dale E
通讯作者：
Bjorling, Dale E

Estrogen receptor 1 expression and methylation of Esr1 promoter in mouse fetal prostate mesenchymal cells induced by gestational exposure to bisphenol A or ethinylestradiol.

妊娠期暴露于双酚 A 或炔雌醇诱导的小鼠胎儿前列腺间充质细胞中雌激素受体 1 的表达和 Esr1 启动子的甲基化。

DOI：
发表时间：
2019-07
期刊：
影响因子：
3.8
作者：
Bhandari, Ramji K;Taylor, Julia A;Sommerfeld;Tillitt, Donald E;Ricke, William A;Vom Saal, Frederick S
通讯作者：
Vom Saal, Frederick S