The major goal of this proposal is to determine the cellular and molecular mechanisms responsible for activation of extracellular matrix genes in bladder fibrosis. Congenital and acquired obstructive uropathies, as the sequelae to neurologic lesions (myelomeningocele, tethered cord syndrome) or physical alteration (posterior urethral valves, benign prostatic hyperplasia, radiation therapy) can result in fibrosis of the bladder wall. The applicant has demonstrated that the terminal response is an accumulation of type III collagen in an abnormal location and an alteration in the ratio of types III to I collagen. To evaluate potential molecular control mechanisms responsible for bladder fibrosis, she will utilize a cell culture model system consisting of human bladder wall cells (detrusor smooth muscle cells and lamina propria fibroblasts) and bladder wall cells from mice which carry genetic mutations in the potential regulatory pathway proteins, transforming growth factor-beta (TGFB) and angiotensin. She will test the hypothesis that extracellular matrix changes in bladder wall cells are regulated by expression of transforming grow factor-beta via a cascade mechanism involving a positive feedback response of angiotensin. She will determine the role of these tissue factors in regulating cell growth (hyperplasia), cell enlargement (hypertrophy) and extracellular matrix gene and protein expression. These experiments will allow determination of the molecular and biochemical impact of each stimulus on a given cell type to determine further what role each cell type within the bladder wall contributes to the pathologic process. In vivo model of mice which have been genetically manipulated to produce less type I collagen or type III collagen, thereby producing a bladder model in which the normal type III: type I collagen ratio has been altered. Using length-tension studies and whole bladder cystometry on these genetically altered bladders; biochemical alterations will be correlated to physiologic functional properties (bladder compliance). We will initiate studies in vivo and in vitro to attempt to identify signaling molecules and transcription factors, which are part of the signaling pathways, which lead to bladder fibrosis.
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