Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a multi-symptomatic clinical problem that involves pain lasting more than 3 months and leads to urinary voiding dysfunction. There are few therapeutic options due to an incomplete understanding of its etiology and pathogenesis. Studies conducted in our laboratory revealed that mast-cell tryptase activation of protease-activated receptor 2 (PAR2) is directly linked to chronic pelvic pain in mice with experimental autoimmune prostatitis (EAP), a mouse model that mimics aspects of CP/CPPS. However, to date, the typtase-PAR2 axis has not been explored as a potential mediator of urinary symptoms reported by CP/CPPS patients. The proposed research project seeks to investigate the link between tryptase-PAR2 axis and urinary voiding dysfunction in a mouse model of CP/CPPS. Preliminary studies presented in this research proposal revealed that PAR2 may be involved in urinary voiding dysfunction. Briefly, data showed that mice with EAP have increased urinary frequency. Also, the prostate of mice with EAP have increased expression of alpha-smooth muscle actin (a-SMA), a fibrosis marker. In contrast, PAR2 knockdown (KO) with EAP do not show changes to urinary frequency and the prostate showed no change in a-SMA expression. In addition, we report that sensitization of dorsal root ganglia due to PAR2 activation occurs in mice with EAP, suggesting that cross-organ sensitization between the prostate and bladder may lead to urinary symptoms. Based on the preliminary data we hypothesize that the mast cell tryptase-PAR2 axis is a novel regulator of prostate fibrosis and sensitization that leads to bladder dysfunction. The proposed research project will address the hypothesis using the following specific aims: 1) Determine the role of tryptase activation of PAR2 in the prostate on bladder dysfunction and 2) determine the effect of the tryptase-PAR2 axis on cross-organ sensitization in DRG shared by the prostate and bladder. Overall, the results from these aims will elucidate our understanding of the induction of urinary symptoms in CP/CPPS patients and identify a novel therapeutic target for treating urinary voiding dysfunction.
This application seeks to explore novel mechanisms that lead to urinary symptoms associated with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) via a mouse model. The successful completion of this project will significantly impact our current understanding of the mechanisms of action associated with urinary symptoms and chronic pain of the prostate and reveal new therapeutic targets for CP/CPPS.
|Roman, Kenny; Murphy, Stephen F; Done, Joseph D et al. (2016) Role of PAR2 in the Development of Lower Urinary Tract Dysfunction. J Urol 196:588-98|