AGING, PROTEIN KINASE C AND SEROTONIN RELEASE

衰老、蛋白激酶 C 和血清素释放

• 批准号: 3118916
• 负责人: EITAN FRIEDMAN
• 金额: $ 9.72万
• 依托单位: ALLEGHENY UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3118916
• 关键词: aging; animal old age; brain metabolism; dietary control; enzyme substrate; exocytosis; gel electrophoresis; genetic strain; laboratory rat; longevity; mature animal; neurotransmitter metabolism; nutrition of aging; nutrition related tag; physiology; platelets; protein kinase C; radiotracer; serotonin; tritium

Aging is associated with changes in the release of neurotransmitter substances from central and peripheral nerve terminals and in the secretion of hormones from glandular tissues. These alterations may underlie the functional deficits which are often noted during the aging process and suggest an age- associated alteration in the exocytotic process. Recent studies in a number of laboratories including our own, have described the involvement of protein kinase C-mediated phosphorylation in the modulation of stimulated release of biologic substances. In preliminary studies performed in Fisher-344 rats, we have found marked age-related deterioration in the ability of protein kinase C to modulate release of brain serotonin. In the present application, we propose to explore the responsiveness to protein kinase C activation of serotonin release in brain and blood platelets as (1) a biological marker of aging, and (2) a tool for assessing physiological aging during interventions which aim to improve longevity such as dietary restriction. Specifically, we propose to (1) precisely define the age dependency of the PKC effect in two strains of rats and their Fl hybrids, which have been fed ad libitum or were food restricted, (2) test the generalizability of the effect in other neurotransmitter systems, and (3) elucidate the molecular mechanisms which underlie the loss in protein kinase C mediated response. Understanding of the fundamental role of PKC in exocytosis and how it is altered during aging will be valuable as a biologic marker of aging and a tool for assessing potential interventions of the aging process. This biologic marker, when examined in blood platelets is easily accessible for use and testing in humans.

老化与发布中的变化有关， 来自中枢和外周神经的神经递质物质 末端和腺体组织分泌激素。 这些改变可能是功能缺陷的基础， 在衰老过程中经常被注意到，并表明一个年龄- 胞吐过程中的相关改变。 的近期研究 包括我们自己在内的一些实验室已经描述了 蛋白激酶C介导的磷酸化参与 调节生物物质的刺激释放。 在 在Fisher-344大鼠中进行的初步研究，我们发现 与年龄相关的蛋白激酶功能的明显退化 调节大脑5-羟色胺的释放。 本 应用，我们建议探索蛋白质的反应性 激酶C激活脑和血液中5-羟色胺释放 血小板作为（1）衰老的生物标志物，和（2）用于 在干预期间评估生理老化， 改善寿命，如限制饮食。 我们特别 建议（1）准确定义PKC的年龄依赖性 在两个品系的大鼠和它们的F1杂种中的作用， 自由进食或食物限制，（2）测试 这种效应在其他神经递质系统中的普遍性， （3）阐明其分子机制 蛋白激酶C介导的应答丧失。 理解 PKC在胞吐作用中的基本作用及其改变 作为衰老的生物标志物， 评估衰老过程潜在干预措施的工具。 当在血小板中检查时，这种生物标志物很容易被 可用于人体并进行测试。