AGING, PROTEIN KINASE C, AND SEROTONIN RELEASE

衰老、蛋白激酶 C 和血清素释放

• 批准号: 2049860
• 负责人: EITAN FRIEDMAN
• 金额: $ 22.92万
• 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 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2049860
• 关键词: G protein; aging; biological signal transduction; biomarker; brain metabolism; dietary control; enzyme activity; enzyme substrate; genetic strain; immunoprecipitation; inositol phosphates; laboratory rat; lymphocyte; membrane proteins; neurotransmitter metabolism; neurotransmitter receptor; northern blottings; nutrition of aging; nutrition related tag; phosphatidylinositols; phosphorylation; platelets; protein kinase C; protein transport; receptor coupling; serotonin; thin layer chromatography; western blottings

The present, competing continuation application aims to continue to develop and test biomarkers of aging in animals obtained from the NIA/NCTR colony. In investigations funded by this grant we have examined age associated alterations in the effect of protein kinase C (PKC) activation on serotonin release in brain slices. We have also examined activity of and translocation of PKC, PKC mediated phosphorylation of membrane proteins, and of the specific membrane PKC substrate, GAP-43. In addition, a number of neurotransmitter-stimulated signal transduction systems have been studied during aging. These include, membrane G protein activation, phosphoinositide hydrolysis and PKC translocation. In these investigations we have observed that diet restriction prevents or retards age-associated changes in some but not all the studied parameters. The investigations to date strongly suggest and lead us to hypothesize that coupling of neurotransmitter receptors to various membrane transduction systems is compromised progressively during aging and that life long diet restriction can prevent, delay or not influence these processes. The proposed investigations specifically aim to (1) further define age related markers associated with neurotransmitter-activated signal transduction systems,. (2) continue to test the effect of diet restriction on these biomarkers, (3) extend the development of blood platelet and lymphocyte as models in studies of transmembrane signal transduction systems-PKC translocation, G protein activation, and phosphoinositide hydrolysis. Experiments are also proposed to explore the molecular mechanisms which underlie these age and diet related changes. In addition, the generalizability of the above systems as biomarkers in aging organisms will be tested in both male and female rats of the following genotypes: F344, B-N and FXB-N hybrids. The proposed investigations will enhance our understanding of the fundamental role of signal transduction in regulating cellular physiology during aging and its applicability in assessing potential interventions of aging processes. The studies will also examine the suitability of these markers for human investigations in easily accessible blood cells.

目前，与之竞争的延续申请旨在继续 开发和测试动物衰老的生物标记物 NIA/NCTR菌落。在由这笔拨款资助的调查中，我们审查了 蛋白激酶C(PKC)作用的年龄相关性变化 激活脑片中5-羟色胺的释放。我们还检查了 蛋白激酶C的活性和转位，蛋白激酶C介导的磷酸化 膜蛋白，以及特定的膜PKC底物GAP-43。 此外，一些神经递质刺激的信号转导 人们在老化过程中对系统进行了研究。其中包括，膜G 蛋白活化、肌醇磷脂水解酶和蛋白激酶C转位。 在这些调查中，我们观察到限制饮食可以防止 或延缓部分但不是所有研究对象的年龄相关变化 参数。到目前为止的调查强烈建议并引导我们 假设神经递质受体与不同的 膜转导系统在老化过程中逐渐受损 而终身节食可以预防、推迟或不影响 这些过程。拟议的调查具体目标是：(1) 进一步定义与以下各项相关的年龄相关标记 神经递质激活的信号转导系统。(二)继续 测试饮食限制对这些生物标志物的影响，(3)扩大 以血小板和淋巴细胞为模型的研究进展 跨膜信号转导系统--PKC转位、G蛋白 活化，以及磷脂酰肌醇的水解。实验也是 建议探索这些年龄和年龄背后的分子机制 与饮食相关的变化。此外，上述内容的概括性 作为老化生物体生物标志物的系统将在男性和 雌性大鼠：F344、B-N和FXB-N杂交种。这个 拟议的调查将加深我们对 信号转导在细胞生理调控中的作用 老龄化及其在评估潜在老龄化干预措施中的适用性 流程。这些研究还将检验这些措施的适用性。 在容易接触的血细胞中用于人类研究的标志物。