The urinary bladder is a smooth muscle organ whose function is to periodically expel the urine via a voluntarily initiated highly coordinated sustained contraction. Similar to other smooth muscles the contractile function of the bladder is mediated by energy generated by the metabolism of intracellular substrates. Any pathological process which interferes with substrate utilization and energy production would result in serious impairment of bladder function. The proposed studies can be separated into three interrelated areas: 1) Detailed studies on the relationships among intracellular energetics, metabolism, and contraction in the normal bladder. These projects include a detailed study of the relationship between calcium movement and the contractile response to specific contractile agonists. 2) The effects of specific experimental pathologies (partial outlet obstruction, acute overdistension, and ischemia) on bladder biochemistry, metabolism, and how they relate to alterations in contractile function. 3) Correlation of the biochemical and contractile effects of the specific pathologies with alterations in bladder morphology. These studies include the identification and localization of the specific proteins which are modified during the response to each experimental uropathology. For these studies, we will apply current techniques in protein chemistry, quantitative autoradiography and morphometry to differentiate hypertrophy from hyperplasia. The first two areas are extensions of the projects completed during the current grant period. The third area is new, and requires the application of novel techniques in the study of urinary bladder function and the response of the urinary bladder to specific experimental pathologies. In this regard, we have added two senior scientists who have extensive experience in smooth muscle protein chemistry and molecular biology. Our long-range goals include: 1) The identification of specific metabolic defects that can either cause specific bladder pathologies, or result from specific pathologies, and 2) The identification of the cellular mechanisms that control the response of the bladder to specific pathological insults. 3) Determining whether the changes that accompany specific pathologies are reversible and, to what extent they may be reversed. 4) Defining the relationships between age and both the severity of the changes induced by specific uropathies and their reversibility. The proposed studies are designed to generate new information on the relationships between bladder metabolism (energetics), bladder contractile function, and bladder morphology. This information will be extremely valuable in increasing our understanding of the biochemical, metabolic, and functional changes that accompany the development of certain bladder pathologies.
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