Role of Nitric Oxide in Interstitial Cystitis

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DESCRIPTION (provided by applicant): Recent evidence has revealed that both afferent nerves and urothelial cells exhibit a number of common properties including the expression of certain receptors and ion channels. Interstitial cystitis (IC) is a chronic painful condition of the urinary bladder in which there are no proven etiologies and no effective treatments that are able to eradicate the symptoms, which include urinary frequency, urgency, nocturia and pain. There is a comparable disease in cats, termed feline interstitial cystitis (FIC), which demonstrates nearly all of the characteristics of human IC including most if not all of the symptoms. We have identified a number of abnormalities in both the urothelium (alterations in barrier function, increased responsiveness to chemical and mechanical stimuli) as well as in afferent nerves (increased response to chemical and mechanical stimuli including different firing properties) in FIC. Additional findings support a general hypothesis that alterations in bladder afferent neurons as well as in urothelial cells may be part of the etiology of FIC. Using a multidisciplinary approach including molecular biology, measurement of transmitter release, electrophysiology and imaging techniques using photodiode arrays, our goals are to further understand the signaling pathways underlying the changes observed in both afferent and urothelial function, as well as signaling mechanisms responsible for various cell-cell interactions and how these mechanisms may be altered in FIC. Aim #1 will evaluate the mechanism by which FIC alters "sensor" and "transducer" functions in urothelial cells. The premise is that a common defect in autocrine signaling/ intracellular Ca2+ (release/sequestration) could be a key contributor to the symptoms of FIC. Such changes could underlie alterations in the "sensor" (i.e. ability to respond to thermal, mechanical and chemical stimuli) as well as "transducer" (i.e. ability to release chemicals) function of urothelium. Aim #2 will evaluate whether urothelial cells and/or sensory neurons exhibit similar alterations in ion channel expression/function in FIC. We will use patch clamp recording to evaluate whether similar changes in channel responsiveness occur in both cell types in FIC. Aim #3 will evaluate the effect of FIC on cell-cell interactions. We will examine how FIC can influence urothelial proliferation/differentiation as well as mechanisms of urothelial communication. Understanding the mechanisms contributing to and maintaining these types of changes may provide important insights for the identification of novel targets for the future clinical management of IC.