Interstitial Cystitis (IC) is a chronic irritable voiding syndrome of unknown etiology. Urinary frequency, urgency, nocturia, suprapubic pressure, and bladder/pelvic pain characterize this condition and there are no predictably effective treatments. Thus, many suffer with incapacitating symptoms for the rest of their lives. We believe that a small animal model will greatly enhance progress since pathophysiologic mechanisms can be dissected and therapeutic strategies developed in a far more controlled environment than the clinic. A model of IC must display features common to the clinical conditions, including chronicity, key elements of the symptom complex, and common pathophysiologic alterations. One etiologic hypothesis is that an urothelial barrier defect exists permitting urinary constituents unusual access to the tissues of the bladder wall. Whether this is an initiating event or the result of other perturbations is controversial, but most lines of evidence support the existence of a barrier deficiency in the clinical syndrome. To generate a small animal model to test the hypothesis that there is a relationship between a barrier defect and irritable voiding patterns, we have developed quantitative methods to evaluate the interplay of bladder permeability with void volume and frequency in mice. We will monitor plasma fluorescein following intravesical administration to assess the integrity of the bladder permeability barrier. We will use computerized balances to measure void volume and frequency within and across days. We will induce chronic cystitis by continuous exposure of the urothelium to agents that disrupt the bladder lining by implanting indwelling bladder catheter in each mouse. This will allow us to determine the relationship between altered bladder permeability and micturition frequency and volume. We will attempt to prevent and/or reverse these chronic barrier defects with several drugs (heparin, pentosan polysulfate and hyaluronic acid) and see what effect they have on permeability and voiding patterns. Finally, we will attempt to generate a transgenic mouse model of IC by targeting the expression of a secreted form of mouse protamine-1 (sMP1) to the transitional epithelium and evaluate these animals in our system.
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