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: 3483719
• 负责人: ROBERT M WEISS
• 金额: $ 23.6万
• 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 1995-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3483719
• 关键词: G protein; adenylate cyclase; adrenergic receptor; aging; autoradiography; calcium channel blockers; calcium flux; calcium indicator; cell membrane; fluid; fluorescent dye /probe; guinea pigs; hormone receptor; hormone regulation /control mechanism; human tissue; inositol phosphates; laboratory rabbit; membrane lipids; membrane structure; muscarinic receptor; muscle contraction; muscle function; neuropharmacologic agent; potassium channel; receptor binding; second messengers; sex hormones; smooth muscle; urinary incontinence; urinary tract

Age-dependent abnormalities in the function of urinary tract 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 membrane structure or composition. The unifying hypothesis of this proposal is that aging causes changes in the biochemical and functional properties of urinary tract smooth muscle, and that these changes may in turn influence the response of these tissues to pharmacologic manipulation and pathologic insult. The long-term objective is to determine both how and why age affects the function of urinary tract smooth muscle. To achieve this goal, we will study changes in ureteral-vesical function with age at the level of 1) signal recognition (hormone-receptor complex); 2) signal transmission (transduction of the signal generated by the interaction of an agonist or hormone with a receptor from the outside of the plasma membrane to the inside of the cell where a biochemical and ultimately a physiologic event occurs); and 3) signal functional response (response to the transmitted signal as measured by changes in contractile force). We plan to: 1) define the physiological parameters involved in receptor regulation, i.e., the regulatory effects of gonadal hormones on the receptor-effector system, 2) characterize and localize autonomic and calcium antagonist receptor subtypes 3) determine the regulatory effect of G-proteins in the transduction of the hormone-receptor signal in adrenergic, muscarinic cholinergic, and calcium antagonist receptor systems, 4) determine how changes in membrane structure and composition that occur with aging affect the functional response of urinary tract smooth muscle, 5) determine the role of the second messengers, i.e., cyclic AMP, cyclic GMP, Ca++ and the products of inositol phospholipid metabolism (inositol trisphosphate, IP3, and diacylglycerol, DG) in the age-dependent functional changes of urinary tract smooth muscle, and 6) determine how age-dependent changes in signal recognition and signal transmission affect the functional response to Ca++ and its agonists and antagonists, membrane perturbers, and potassium channel agonists and antagonists. The determination of how age affects the function of urinary tract smooth muscle and the response of the smooth muscle to pharmacologic agents may provide a rationale for the development of new drugs for the treatment of pathologic states.

尿路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，并且/或可能导致 与其由此产生的医学，心理，社会学的尿失禁， 和经济影响。这些功能变化可能是由 调节机制的改变或膜结构的变化 或成分。该提议的统一假设是衰老 导致尿的生化和功能特性变化 道平滑肌，这些变化可能会影响 这些组织对药理操作和病理的反应 侮辱。长期目标是确定年龄的方式和原因 影响尿路平滑肌的功能。为了实现这一目标， 我们将研究输尿管维护功能的变化，年龄在 1）信号识别（激素受体复合物）； 2）信号传输 （通过激动剂的相互作用或 激素带有从质膜外部的受体到达的受体 在细胞内生化和最终生理事件的内部 发生）； 3）信号功能响应（对传输的响应 信号通过收缩力的变化来衡量）。我们计划：1）定义 受体调节涉及的生理参数，即 性腺激素对受体效应系统的调节作用，2） 表征和定位自主和钙拮抗剂受体 亚型3）确定G蛋白在 激素受体信号的转导肾上腺素，毒蕈碱 胆碱能和钙拮抗剂受体系统，4）确定如何 衰老影响发生的膜结构和组成的变化 尿路平滑肌的功能反应，5）确定 第二使者的作用，即环状AMP，环状GMP，Ca ++和 肌醇磷脂代谢的产物（肌醇三磷酸盐，IP3， 和二酰基甘油，DG）在尿的年龄依赖性功能变化中 道平滑肌和6）确定信号的年龄依赖性变化 识别和信号传递会影响对CA ++的功能响应 及其激动剂和拮抗剂，膜perturber和钾 渠道激动剂和对手。确定年龄如何影响 尿路平滑肌的功能和平滑的响应 药理学剂的肌肉可能为开发提供理由 用于治疗病理状态的新药。