Neurotrophic Mechanisms in LUT Plasticity with Cystitis

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DESCRIPTION (provided by applicant): Interstitial cystitis (IC) is a chronic inflammatory bladder disease syndrome characterized by urinary frequency, urgency, suprapubic and pelvic pain. Although the etiology and pathogenesis of IC are unknown, numerous theories including; infection, autoimmune disorder, toxic urinary agents, deficiency in bladder wall lining and neurogenic causes have been proposed. Pituitary adenylate cyclase activating polypeptide (PACAP) exerts diverse and prevalent roles in the lower urinary tract (LUT). Sensory fibers expressing PACAP have been identified in the bladder wall and in suburothelial plexuses, PACAP expression in the micturition reflex pathway is upregulated following chronic cystitis and pharmacological agents that block PACAP receptor function reduce bladder overactivity after cystitis. PACAP expression can be regulated by neurotrophins; conversely, recent studies have also suggested that PACAP may regulate neurotrophin receptor tyrosine kinase expression and activation. Cystitis markedly alters the profile of neurotrophin expression in bladder tissues. Thus, the resulting changes in target organ growth factor levels may drive the neurochemical and functional plasticity in the micturition pathway with cystitis. The overall hypothesis for our work is that pain and micturition dysfunction in IC involves an alteration in bladder smooth muscle, urothelium and sensory physiology. The central hypothesis is that the VIPIPACAP system is a prominent modulator of bladder sensation and function and the inflammation-induced changes in neurotrophic factors and/or neural activity arising in the bladder alter PACAP/PACAP receptor expression in LUT to mediate altered micturition function in IC. The following three aims test these hypotheses. 1). To characterize PACAP and PACAP receptor expression in urothelium, bladder smooth muscle and bladder afferent cells in the lumbosacral DRG; 2). To establish the functional relationships between PACAP and neurotrophin systems in the normal micturition reflex pathway and after cystitis.; 3). To evaluate the physiological roles of PACAP and neurotrophins in the micturition reflex pathway using PACAP knockout mice.