Chronic pelvic pain is the hallmark of patients with chronic pelvic pain syndrome (CPPS), a non- bacterial category of prostatitis that is a significant source of morbidity in American men. The etiology and pathogenesis of CPPS remains unknown but has been postulated to include a multitude of causes. The lack of convenient biomarkers and a better understanding of CPPS pathophysiology have complicated disease diagnosis and therapy. We identified MCP-1 and MIP-11 as potential biomarkers in expressed prostatic secretions (EPS) of patients with CPPS. MCP-1 and MIP-11 levels in EPS identified CPPS patients with an accuracy of 90% and MIP-11 levels were correlated with the clinical pain subdomain score of the National Institutes of Health Chronic Prostatitis Symptom Index. We utilized quantitative measures of pelvic pain in murine models of prostatitis to characterize prostate-specific, chronic pelvic pain reminiscent of human CPPS. Intra-prostatic expression of MIP-11 and MCP-1 at 20 days was increased in the murine model. Anti-MCP-1 or anti-MIP-11 neutralizing antibody significantly reduced the development of chronic pelvic pain in mice with Anti-MCP-1 also being effective therapeutically. In addition to chemokine upregulation, increased numbers of mast cells that were activated was also observed. Taken together, these studies lead us to hypothesize that chemokines such as MCP-1 and MIP-11 contribute to the recruitment and activation of mast cells leading to peripheral neuronal sensitization and development of chronic pelvic pain. We will pursue our hypothesis with four specific aims. We will perform rigorous clinical studies to validate the use of MCP-1 and MIP-11 and mast cell tryptase as biomarkers for CPPS in humans and correlate their levels with CPPS symptoms. We will quantify mast cells and localize MCP-1 and MIP-11 expression in retrospectively collected human prostate tissue sections. The source of MCP-1 and MIP-11 expression and the role of mast cells will be dissected in the animal model. In vitro culture models will examine prostate-epithelia/stroma interactions with mast cells. Finally, we will test the efficacy of targeted therapies that inhibit MCP-1, MIP-11 and mast cell function in reducing chronic pelvic pain. This project will lay the ground for future translational studies of therapies that target the mechanisms underlying chronic pelvic pain in CPPS.
Chronic pelvic pain is the hallmark of patients with chronic pelvic pain syndrome (CPPS), a non-bacterial category of prostatitis that is a significant source of morbidity in American men. The cause of CPPS is unknown and there is a lack of convenient biomarkers for diagnosis of this syndrome. This project will validate biomarkers for the diagnosis of CPPS and also perform studies to understand the mechanisms behind disease symptoms. Finally, this project will test the efficacy of new therapies targeting chronic pelvic pain in animal models.
|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|
|Wong, Larry; Done, Joseph D; Schaeffer, Anthony J et al. (2015) Experimental autoimmune prostatitis induces microglial activation in the spinal cord. Prostate 75:50-9|
|Murphy, Stephen F; Schaeffer, Anthony J; Done, Joseph et al. (2015) IL17 Mediates Pelvic Pain in Experimental Autoimmune Prostatitis (EAP). PLoS One 10:e0125623|
|Murphy, Stephen F; Schaeffer, Anthony J; Thumbikat, Praveen (2014) Immune mediators of chronic pelvic pain syndrome. Nat Rev Urol 11:259-69|
|Roman, Kenny; Done, Joseph D; Schaeffer, Anthony J et al. (2014) Tryptase-PAR2 axis in experimental autoimmune prostatitis, a model for chronic pelvic pain syndrome. Pain 155:1328-38|
|Quick, Marsha L; Done, Joseph D; Thumbikat, Praveen (2013) Measurement of tactile allodynia in a murine model of bacterial prostatitis. J Vis Exp :e50158|
|Quick, Marsha L; Wong, Larry; Mukherjee, Soumi et al. (2013) Th1-Th17 cells contribute to the development of uropathogenic Escherichia coli-induced chronic pelvic pain. PLoS One 8:e60987|
|Quick, Marsha L; Mukherjee, Soumi; Rudick, Charles N et al. (2012) CCL2 and CCL3 are essential mediators of pelvic pain in experimental autoimmune prostatitis. Am J Physiol Regul Integr Comp Physiol 303:R580-9|
|Done, Joseph D; Rudick, Charles N; Quick, Marsha L et al. (2012) Role of mast cells in male chronic pelvic pain. J Urol 187:1473-82|
|Rudick, Charles N; Berry, Ruth E; Johnson, James R et al. (2011) Uropathogenic Escherichia coli induces chronic pelvic pain. Infect Immun 79:628-35|
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