AGE DEPENDENT FACTORS IN URETERAL-VESICAL FUNCTION

尿路平滑肌功能的增龄性异常 可能导致肾脏结构和功能恶化和/或可能导致 大小便失禁以及由此产生的医学、心理学、社会学、 以及对经济的影响。这些功能变化可能是由于 调节机制的改变或膜结构的变化 或者是构图。这一提议的统一假设是，衰老 引起尿液生化和功能性质的改变 而这些变化又可能反过来影响 这些组织对药物操作和病理的反应 侮辱。长期目标是确定衰老的方式和原因。 影响尿路平滑肌的功能。为了实现这一目标， 我们将在以下水平研究输尿管膀胱功能随年龄的变化 1)信号识别(激素-受体复合体)；2)信号传递 (通过激动剂或激动剂的相互作用产生的信号的传递 荷尔蒙与一个受体从质膜外部到 在细胞内，生物化学和最终的生理事件 发生)；以及3)信号功能响应(对传输的响应 通过收缩力的变化来测量信号)。我们计划：1)定义 参与受体调节的生理参数，即 性腺激素对受体-效应系统的调节作用2) 自主神经和钙拮抗剂受体的特性和定位 亚型3)决定G-蛋白在体内的调节作用 激素受体信号在肾上腺素能毒碱能体内的转导 胆碱能和钙拮抗剂受体系统决定了 随着衰老而发生的膜结构和组成的变化影响 尿路平滑肌的功能反应，5)决定 第二信使，即cAMP、cGMP、Ca++和 肌醇磷脂代谢产物(三磷酸肌醇，IP3， 和二酰甘油(DG)在增龄相关尿功能改变中的作用 6)决定信号随年龄变化的方式 识别和信号传递影响对钙离子的功能反应 及其激动剂和拮抗剂、膜干扰剂和钾 通道激动剂和拮抗剂。确定年龄是如何影响 尿路平滑肌的功能及其对尿路的反应 肌肉到药理作用的因素可能为发展提供了理论基础 治疗病理状态的新药。

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.