CONTROL OF URNIARY BLADDER FUNCTION--MOLECULAR APPROACH

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The urinary bladder responds to specific pathological and surgical situations with major alterations in bladder mass, capacity, compliance, and response to pharmacological agents. For example, partial outlet obstruction induces a rapid and marked increase in bladder mass, significant decreases in bladder capacity and compliance, and a decrease in bladder function (ability to contract and/or empty). Unilateral ischemia induces changes similar to those observed for outlet obstruction. Acute overdistention initiates many of the pathological changes in bladder contraction and function that occur with outlet obstruction, although these changes quickly resolve within two weeks after overdistension. By contrast, bladder diversion induces a rapid decrease in bladder mass (atrophy), decreases in capacity and compliance, and a decreased contractile response to field stimulation and pharmacological agents. Removal of the stress (removal of the outlet obstruction or re-implantation of the ureters following diversion) induces a rapid and nearly complete reversal of the changes described above. Our studies up to this time have characterized the urodynamic, physiological, pharmacological, morphological, and metabolic responses to several experimentally induced pathologies including partial outlet obstruction, unilateral ischemia, acute overdistension, and urinary diversion. Recently, we have initiated a series of studies at sub-cellular levels which are directed at the identification of the early signals which initiate the various responses to stress. We propose to correlate the time course and magnitude of the initial events in gene activation with cellular changes in protein chemistry, cell growth, and cell division. The long term goal of these studies is to determine the cellular mechanisms by which bladder structure and function are altered by specific patholologies. Our initial studies on gene expression demonstrated that partial outlet obstruction stimulated the expression of a variety of specific genes which control cell growth/division, and protein synthesis. These genes included N-Ras, C-Myc, beta-Actin, heat shock protein-70 (HSP- 70), and basic fibroblast growth factor in association with a decrease in transforming growth factor beta. The short term goals of the current proposal include: 1) Determination of the sequence of changes in gene expression stimulated by partial outlet obstruction: 1, 2, 4, 8, 16, 24 hours, 3, 5, 7, and 14 days after induction of the pathology. 2) Demonstration of the tissue/cellular locale(s) of up- or downregulated gene expression in specific cellular elements in the bladder base and body (eg. in mucosa, submucosa, muscularis, and serosa) using in situ hybridization, and immunocytochemistry. 3) Quantitative correlations of transcriptional with translational events in altered tissue/cells for substances such as basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF), heat shock proteins 70 (HSP-70) and 90 (HSP-90), and the specific cytoskeletal proteins vimentin, desmin, and actin. 4) Effects of specific gene products with cell growth and division (using quantitative morphometry and thymidine incorporation into DNA).