CTGF drives voiding dysfunction through expression of collagen in periurethral SRD5A2+ fibroblasts

CTGF 通过尿道周围 SRD5A2 成纤维细胞中胶原蛋白的表达驱动排尿功能障碍

基本信息

批准号：
10700927
负责人：
Douglas William Strand
金额：
$ 21.8万
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/10700927
关键词：
Address Adult Age Aging Antibodies Applications Grants Area Benign Bladder Blocking Antibodies COL1A2 gene Canis familiaris Cells Collagen Communities Computer software Cryopreserved Cell Data Data Set Databases Deposition Development Disease Elderly Enterobacteria phage P1 Cre recombinase Etiology Failure Fibroblasts Fibrosis Frequencies Functional disorder Funding Funding Opportunities Future Generations Goals Growth Factor Overexpression Human Inflammation Inflammatory Instruction Investigational Drugs Knowledge Link Lower urinary tract Manuscripts Maps Mediating Mediator Medical Methods Molecular Mouse Strains Mus Muscle Obstruction Oxidoreductase Pathogenesis Pathologic Pathology Patients Pharmaceutical Preparations Phase II Clinical Trials Pilot Projects Process Production Proliferating Prostate Prostatic Reagent Relaxation Research Research Personnel Research Project Grants Resources SRD5A2 gene Smooth Muscle Stains Steroids Stromal Cells Symptoms Teaching Hospitals Testing Tissue Banks Tissues Treatment Failure Urethra Urinary Retention Urinary tract Urology Visualization software blocking factor cell type connective tissue growth factor cost data visualization density idiopathic pulmonary fibrosis improved innovation insight lower urinary tract symptoms male member men mouse model new therapeutic target primary endpoint segregation single-cell RNA sequencing therapeutic target transcriptome sequencing transcriptomics urinary web site

项目摘要

PROJECT SUMMARY- PROJECT 2 Lower urinary tract symptoms cost more than $4 billion annually. Though current medical therapies reduce prostate volume and relax smooth muscle to address symptoms, existing therapies are not curative. Three things are clear: (1) male lower urinary tract symptoms derive from multiple underlying pathologies, not just prostatic enlargement or muscle dysfunction (2) current therapies do not effectively target pathologies outside of benign enlargement and smooth muscle dysfunction, and (3) there is a need to identify additional mechanisms underlying lower urinary tract symptom etiology to formulate therapies that are more effective. 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 lower urinary tract symptoms (LUTS). Prostatic collagen accumulation (fibrosis) has been identified as a cause of male lower urinary tract symptoms. Prostatic collagen accumulation has been linked to prostatic stiffness, lower urinary tract symptoms, and failed medical treatment. It will not be possible to treat prostatic fibrosis and associated voiding dysfunction until prostatic collagen-producing cells are identified. The goal of this project is to tackle this challenge by pinpointing the cellular and molecular origins of pathological collagen production in the prostate. A subpopulation of human prostatic fibroblasts residing in close proximity to the urethra and expressing steroid five alpha reductase type II (SRD5A2) has been identified, supporting the central hypothesis that inflammation causes these fibroblasts to proliferate, synthesize connective tissue growth factor (CTGF) and produce collagen. Collagen accumulation in turn leads to urethral stiffening, bladder outlet obstruction, urinary retention, and voiding dysfunction. The proposed studies offers essential insight into the pathogenesis of prostatic fibrosis, a mechanism of lower urinary tract symptom medical therapy failure. Aim 1 will test the hypothesis that inflammation increases human prostatic SRD5A2+ fibroblast frequency and drives CTGF and COL1A2 expression. Aim 2 tests whether inflammation increases frequency of mouse prostatic Srd5a2+ fibroblasts and whether depletion of these fibroblasts resolves inflammation-mediated collagen accumulation and voiding dysfunction. Aim 3 will test whether CTGF overexpression is sufficient to drive mouse prostatic collagen accumulation and voiding dysfunction and whether an investigational new CTGF blocking drug resolves the problems. The proposed studies will pinpoint CTGF expression in SRD5A2+ fibroblasts as a therapeutic target for treating lower urinary tract symptoms. By establishing mechanistic connections between inflammation, CTGF and COL1A2 abundance, and urinary dysfunction, the studies launch an original line of research into a disease process that is yet-to-be leveraged as a target for medical therapies addressing lower urinary tract symptoms.

项目概要 - 项目 2 尽管目前的药物治疗可减少泌尿道症状，但每年花费超过 40 亿美元。前列腺体积和放松平滑肌来解决症状，现有的疗法没有疗效。很明显：（1）男性下尿路症状源自多种潜在病理，而不仅仅是前列腺增大或肌肉功能障碍 (2) 目前的疗法不能有效地针对良性以外的病理增大和平滑肌功能障碍，并且（3）需要确定其他机制确定下尿路症状的潜在病因，以制定更有效的总体治疗方法。奥布莱恩良性泌尿学研究中心的目标是确定导致尿频降低的机制尿路功能障碍和前列腺相关的下尿路症状（LUTS）。（纤维化）已被确定为男性下尿路症状的原因。与前列腺僵硬、下尿路症状和治疗失败有关。可以治疗前列腺纤维化和相关的排尿功能障碍，直到前列腺胶原蛋白生成细胞被该项目的目标是通过查明细胞和分子起源来应对这一挑战。前列腺中病理性胶原蛋白的产生。靠近尿道并表达类固醇的人类前列腺成纤维细胞亚群已鉴定出五种 II 型 α 还原酶 (SRD5A2)，支持炎症的中心假设导致这些成纤维细胞增殖、合成结缔组织生长因子（CTGF）并产生胶原蛋白。胶原蛋白积聚反过来会导致尿道僵硬、膀胱出口梗阻、尿潴留等。拟议的研究为前列腺纤维化的发病机制提供了重要的见解。下尿路症状药物治疗失败的机制目标 1 将检验以下假设：炎症增加人前列腺SRD5A2+成纤维细胞频率并驱动CTGF和COL1A2 目标 2 测试炎症是否会增加小鼠前列腺 Srd5a2+ 成纤维细胞的频率和这些成纤维细胞的消耗是否可以解决炎症介导的胶原蛋白积累和排尿问题目标 3 将测试 CTGF 过度表达是否足以驱动小鼠前列腺胶原蛋白。蓄积和排尿功能障碍以及正在研究的新型 CTGF 阻断药物是否可以解决该问题拟议的研究将确定 SRD5A2+ 成纤维细胞中的 CTGF 表达作为治疗靶点。通过建立炎症、CTGF 之间的机制联系来治疗下尿路症状。和 COL1A2 丰度以及泌尿功能障碍，这些研究启动了对疾病的原创研究该过程尚未被用作解决下尿路症状的药物治疗的目标。