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

• 批准号: 9921108
• 负责人: Douglas William Strand
• 金额: $ 23.31万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9921108
• 关键词: Address; Adult; Age; Aging; Antibodies; Applications Grants; Area; Benign; Bladder; Blocking Antibodies; COL1A2 gene; Canis familiaris; Cell Extracts; 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; Investigation; Investigational Drugs; Knowledge; Link; Lower urinary tract; Manuscripts; Maps; Mediating; Mediator of activation protein; 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; Research; Research Personnel; Research Project Grants; Resources; SRD5A2 gene; Smooth Muscle; Stains; Steroids; Stromal Cells; Symptoms; Teaching Hospitals; Testing; 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; repository; single-cell RNA sequencing; therapeutic target; transcriptome sequencing; transcriptomics; urinary; web site

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 下尿路症状每年造成的损失超过 40 亿美元。尽管目前的医学疗法减少了 前列腺体积和放松平滑肌来解决症状，现有疗法并不能治愈。三件事 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 肿大或肌肉功能障碍 (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 了解下尿路症状的潜在病因，以制定更有效的治疗方法。首要的 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）。前列腺胶原蛋白堆积 （纤维化）已被确定为男性下尿路症状的原因。前列腺胶原蛋白堆积 与前列腺僵硬、下尿路症状和治疗失败有关。它不会是 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 确定。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。 排尿功能障碍。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，前列腺纤维化是一种 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 表达。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 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 功能障碍。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 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 用于治疗下尿路症状。通过在炎症、CTGF 之间建立机制联系 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。