Age dependent abnormalities in the function of urinary tract urothelium and smooth muscle may lead to deterioration in renal structure and function and/or may result in incontinence with its resultant medical, psychological, sociological and economic implications. These functional changes may result from alterations in regulatory mechanisms or from changes in tissue structure and composition. The unifying hypothesis of this proposal is that aging causes changes in the function of the urinary tract and that these changes in turn influence the response of the tissues to pharmacologic manipulations and to pathologic insults. We have been testing this hypothesis by studying changes in ureteral-vesical function with age and disease at the levels of 1) signal recognition; 2) signal transmission; and 3) signal functional response, and have described age dependent changes in endothelin receptors, inhibitory G-proteins, adenylyl and guanylyl cyclases, neuronal nitric oxide synthase (nNOS) and cGMP dependent phosphodiesterase(s). We now plan to determine the mechanism for these age dependent changes, whether other isoforms are regulated with aging, and whether these age-dependent changes affect smooth muscle and/or urothelial function in the urinary tract. We will: 1) identify, localize and characterize age- and sex hormone-dependent changes in the subtype specificity of endothelin (ET) receptors and of their mRNAs in the urinary tract and determine their effect on urinary tract function; 2) determine the effect of age dependent changes in heterotrimeric G-proteins on downstream enzymatic and functional responses of the urinary tract, and determine if manipulation of cytokines, that are known to increase with aging, can change G-protein levels and affect downstream responses; and 3) determine whether age dependent changes in enzymes which regulate cGMP content, including NOS, G-cyclase and cGMP-dependent PDE, affect urothelial and smooth muscle function of the urinary tract. The determination of how age affects the function of the urinary tract and its response to pharmacologic agents may provide a rationale for the development of new drugs for the treatment of pathologic states.
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