AGE DEPENDENT FACTORS IN URETERAL-VESICAL FUNCTION

尿路尿路上皮和平滑肌功能的年龄依赖性异常可能导致肾脏结构和功能的恶化和/或可能导致尿失禁，并由此产生医学、心理、社会学和经济影响。这些功能改变可能是由于调节机制的改变或组织结构和组成的改变。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操作和病理损伤的反应。我们通过研究输尿管-膀胱功能随年龄和疾病的变化，在信号识别水平上验证了这一假设；2)信号传输；3)信号功能反应，并描述了内皮素受体、抑郁性g蛋白、腺苷酸和鸟苷酸环化酶、神经元一氧化氮合酶（nNOS）和cGMP依赖性磷酸二酯酶(s)的年龄依赖性变化。我们现在计划确定这些年龄依赖性变化的机制，其他亚型是否随年龄增长而调节，以及这些年龄依赖性变化是否影响尿路平滑肌和/或尿路上皮功能。我们将：1)识别、定位和表征尿路中内皮素（ET）受体及其mrna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)确定异源三聚体g蛋白的年龄依赖性变化对尿路下游酶和功能反应的影响，并确定是否操纵已知随年龄增长而增加的细胞因子可以改变g蛋白水平并影响下游反应；3)确定NOS、g -环化酶和cGMP依赖性PDE等调节cGMP含量的酶的年龄依赖性变化是否影响尿路上皮和平滑肌功能。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依据。

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.