MOLECULAR RESPONSE OF THE BLADDER TO OBSTRUCTION

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DESCRIPTION (Adapted from the Applicant's Abstract): Bladder muscle stretch and relaxation during fetal life are required for normal bladder development. A lack of an adequate level of mechanical exercise or volume work or a disruption of the normal patterns of stretch within the bladder wall will lead to biochemical and structural alterations within the bladder muscle and structural proteins ultimately affecting bladder function. The majority of fetal stress conditions are related to urogenital pathologies which occur developmentally, such as posterior urethral valves, functional bladder obstructions secondary to myelomeningocele and oligohydramnios which can affect lung development. The objectives of this study are: 1) to establish an animal model of fetal bladder obstruction and reversal, and the efficacy of surgical interventions, 2) to determine the role of mechanical signals, i.e. stretch, in regulating extracellular matrix synthesis and accumulation in the developing fetal sheep model; 3) to determine the effect of physical obstruction of the developing bladder on matrix and growth factor expression (immediate early genes and TGF-betas, basic FGF, NGF); 4) to determine the parameters and kinetics of matrix and growth factor expression following obstruction reversal; 5) to determine if stretch, in the absence of high pressures induced by obstruction (vesicotomy model), or absence of stretch and volume-work (bilateral nephrectomy) allows the bladder to remodel and maintain itself as a functional organ and 6) to determine the role of the transcription factor, the Wilms tumor gene product (wt-1) in the regulation of bladder development, obstruction and reversal. Physiological measurements of bladder function will be determined by cystometry. Cystometrograms will be correlated with longitudinal analyses of extracellular matrix steady state mRNA and protein expression (amino acid analyses, desmosine analysis ELISA) to evaluate the kinetics of activation or repression, histological and immunohistochemical analyses to determine localization of these proteins during development and any alteration as a result of obstruction. Electron microscopy will be performed to determine if collagen fibril diameter is altered and correlated with changes in thpeIII:type I collagen rations and functional physiologic compliance measurements.