AGE DEPENDENT FACTORS IN URETERAL-VESICAL FUNCTION

输尿管膀胱功能的年龄依赖性因素

• 批准号: 6517119
• 负责人: ROBERT M WEISS
• 金额: $ 32.87万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-02-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6517119
• 关键词: G protein; adenylate cyclase; aging; autoradiography; biological signal transduction; clinical research; cyclic GMP; endothelin; enzyme activity; guanylate cyclase; hormone receptor; human tissue; in situ hybridization; laboratory rabbit; laboratory rat; muscle function; nitric oxide synthase; phosphodiesterases; polymerase chain reaction; receptor binding; smooth muscle; urinary incontinence; urinary tract; urology

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.

泌尿道尿道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恶化和/或可能导致失禁及其由此产生的医学、心理、社会学和经济影响。 这些功能变化可能是由于调节机制的改变或组织结构和组成的变化引起的。 该提议的统一假设是，衰老导致泌尿道功能发生变化，而这些变化反过来又影响组织对药物操作和病理损伤的反应。 我们一直在通过研究输尿管膀胱功能随年龄和疾病的变化在以下水平上检验这一假设：1）信号识别； 2）信号传输； 3) 信号功能反应，并描述了内皮素受体、抑制性 G 蛋白、腺苷酸环化酶和鸟苷酸环化酶、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，其他亚型是否随着衰老而受到调节，以及这些年龄依赖性变化是否影响泌尿道中的平滑肌和/或尿路上皮功能。 我们将： 1) 识别、定位和表征泌尿道内皮素 (ET) 受体及其 mRNA 亚型特异性的年龄和性激素依赖性变化，并确定它们对泌尿道功能的影响； 2) 确定异源三聚体 G 蛋白的年龄依赖性变化对泌尿道下游酶和功能反应的影响，并确定已知随着年龄增长而增加的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 NOS、G-环化酶和 cGMP 依赖性 PDE）的年龄依赖性变化是否影响泌尿道的尿路上皮和平滑肌功能。 确定年龄如何影响泌尿道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依据。