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

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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.