AGE DEPENDENT FACTORS IN URETERAL-VESICAL FUNCTION

尿路上皮和平滑肌功能的年龄相关性异常可能导致肾脏结构和功能的恶化，和/或可能导致大小便失禁，从而产生医学、心理、社会和经济影响。这些功能变化可能是由于调节机制的改变或组织结构和成分的变化造成的。这一建议的统一假设是，衰老导致尿路功能的变化，这些变化反过来影响组织对药物处理和病理侮辱的反应。我们通过研究输尿管膀胱功能随年龄和疾病的变化在1)信号识别；2)信号传递；3)信号功能反应的水平上验证了这一假说，并描述了内皮素受体、抑制性G蛋白、腺苷和鸟苷酸环化酶、神经元型一氧化氮合酶和cGMP依赖的磷酸二酯酶(S)随年龄的变化。我们现在计划确定这些年龄相关性变化的机制，其他亚型是否随着年龄的增长而调节，以及这些年龄相关性变化是否影响尿路的平滑肌和/或尿路上皮功能。我们将：1)鉴定、定位和表征尿路内皮素(ET)受体及其mRNAs亚型特异性的年龄和性激素依赖性变化，并确定其对尿路功能的影响；2)确定年龄相关的异源三聚体G蛋白变化对尿路下游酶和功能反应的影响，并确定细胞因子的操纵是否可以改变G蛋白水平并影响下游反应；3)确定调节cGMP含量的酶，包括一氧化氮合酶、G-环化酶和依赖cGMP的PDE的年龄相关性变化是否影响尿路上皮和尿路平滑肌功能。确定年龄如何影响尿路功能及其对药物的反应可能为开发治疗病理状态的新药提供理论基础。

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.