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

项目概要-项目2 下尿路症状每年花费超过40亿美元。虽然目前的医学治疗减少了 前列腺体积和放松平滑肌来解决症状，现有的疗法是没有治愈性的。三件事 明确：（1）男性下尿路症状来自多种潜在的病理，而不仅仅是前列腺 （2）目前的疗法不能有效地靶向良性肿瘤以外的病理 增大和平滑肌功能障碍，以及（3）需要确定其他机制 潜在的下尿路症状病因，以制定更有效的治疗方法。总体 奥布莱恩良性泌尿学研究中心的目标是确定导致下尿路疾病的机制。 尿道功能障碍和前列腺相关下尿路症状（LUTS）。前列腺胶原积聚 （纤维化）已被确定为男性下尿路症状的原因。前列腺胶原积聚 与前列腺僵硬、下尿路症状和药物治疗失败有关。它不会被 有可能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产生细胞 鉴定该项目的目标是通过精确定位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。 人前列腺成纤维细胞的一个亚群，位于尿道附近并表达类固醇 已经鉴定了5种α还原酶II型（SRD 5A 2），支持了炎症的中心假设， 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。 胶原蛋白的积累反过来又导致尿道硬化、膀胱出口梗阻、尿潴留， 排尿功能障碍这些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SRD 5A 2+成纤维细胞频率并驱动CTGF和COL 1A 2 表情目的2测试炎症是否增加小鼠前列腺Srd 5a 2+成纤维细胞的频率， 这些成纤维细胞的消耗是否解决了炎症介导的胶原积累和排泄 功能障碍目的3将测试CTGF过表达是否足以驱动小鼠前列腺胶原 蓄积和排尿功能障碍，以及研究性新CTGF阻断药物是否解决了 问题拟议的研究将确定SRD 5A 2+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。通过建立炎症之间的机制联系，CTGF 和COL 1A 2丰度，以及泌尿功能障碍，这些研究启动了对一种疾病的原创性研究， 这一过程尚未被用作解决下尿路症状的医学治疗的目标。

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.