Role of TNF in Bladder Inflammation

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DESCRIPTION (provided by applicant): Interstitial cystitis (IC) is a syndrome that afflicts up to 1 million Americans with grave morbidity due to severe pelvic pain and voiding dysfunction. Although IC is often considered a chronic inflammatory disease of the urinary bladder, the etiology of IC is unknown, no effective therapies exist, and no convenient biomarkers exist. The lack of a convenient biomarker complicates both IC diagnosis and monitoring responses to therapy. Recent pathologic studies have shown that patient symptoms are correlated with lesions of the urothelium that lines the bladder and accumulation of mast cells in the underlying lamina propria. Inflammation due to neurogenic mechanisms has been postulated as one mechanism of IC pathogenesis. We developed a mouse model of neurogenic cystitis that recapitulates key aspects of IC including bladder-specific pain, altered bladder physiology, urothelial lesions, and accumulation of lamina propria mast cells. We find that bladder pathology requires expression of RANTES, a mast cell chemokine that is induced in the urothelium by tumor necrosis factor alpha (TNF). Importantly, we find that RANTES is also elevated in IC urines, thus representing a novel urine biomarker for IC. In our murine model, inhibiting RANTES or TNF blocks lamina propria mast cell accumulation and bladder pathology. Therefore, we hypothesize that RANTES is a urinary biomarker that is elevated in a subset of IC patients, and anti-RANTES therapy represents a novel therapeutic target for treating RANTES-associated IC. We will test this hypothesis by first establishing the prevalence of elevated RANTES in urines of IC patients and control groups by taking advantage of our unique access to a cohort of 600 urine samples from a nationwide IC epidemiology study (Aim 1). We will then quantify the efficacy of mechanistically-directed therapies in two complementary murine models. Anti-RANTES and anti-TNF will be evaluated for inhibition of bladder pathology and pathophysiology in acute neurogenic cystitis (Aim 2). Anti-RANTES and anti-TNF will then be evaluated in a chronic, urothelium-specific TNF cystitis model (Aim 3). This innovative approach determining the prevalence of RANTES as a novel chemokine biomarker and then testing rationally directed therapeutic interventions in murine models has a high likelihood of success. This project lays the ground for future clinical studies of IC therapies and provides a novel phenotypic biomarker for genetic studies.Interstitial cystitis (IC) is a syndrome that afflicts up to 1 million Americans with grave morbidity due to severe pelvic pain and voiding dysfunction, yet the etiology of IC is unknown, and no convenient biomarkers exist. This project will determine the prevalence of RANTES as a novel IC biomarker in urines and then quantify the efficacy of mechanistically-directed therapies in murine models.