Numerous conditions exist, in both adults and children, where either functional or anatomic bladder obstruction leads to bladder wall fibrosis resulting in diminished proficiency of the bladder to store and empty urine. These clinical conditions result in significant patient morbidity (e.g., incontinence, renal failure, and ultimately death) and take an enormous financial toll on available medical resources. Because of this clinical significance, we have begun to study the mechanisms that regulate the bladder fibrotic response. The renin-angiotensin system (RAS) and TGFb are known to be mediators of tissue fibrosis in a number of organ systems, however, their function in bladder fibrosis are poorly understood. We have previously shown that aberrations in the RAS are associated with renal maldevelopment and progression of renal fibrosis and loss of function. We have confirmed that surgical bladder obstruction results in bladder thickening and fibrosis which coincides with increased TGFb signaling and extracellular matrix deposition within the bladder wall. Thus, this model appears quite appropriate as a means to study these mediators of bladder fibrosis. We will explore changes that occur in the TGFb isoforms, TGFb receptors, and TGFb downstream mediators in a rodent model of bladder obstruction/fibrosis. In addition, we will investigate whether cellular overexpression of TGFb affects bladder smooth muscle differentiation and extracellular matrix composition. Finally, we will determine the effects of RAS antagonism on TGFb-mediated bladder fibrosis in addition to the effect of cellular TGFB silencing on extracellular matrix composition. Through these studies we hope to delineate signal transduction pathways that regulate the bladder's fibrotic response to obstruction in an attempt to find new targets for intervention. Translation of these findings to human disease processes may prevent the pathologic changes in bladder storage capacity that occurs with many types of bladder dysfunction and reduce the burden of these diseases on society.
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