MECHANISMS OF CELLULAR DEGENERATION IN AGING

衰老过程中细胞退化的机制

• 批准号: 3813666
• 负责人: GARY S LYNCH
• 金额: --
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3813666
• 关键词: aging; brain metabolism; calcium channel blockers; calcium metabolism; cerebellum; electrophysiology; enzyme mechanism; hippocampus; hypothalamus; laboratory rat; lipofuscin; mitochondria; monoclonal antibody; neurochemistry; peptidases; pons; pyruvate dehydrogenase

The goal of this project is to characterize the biochemical events underlying nerve cell degeneration during aging. Specific attention focuses upon two mechanisms, which may be related. Primary emphasis is directed towards calcium-activated proteases (calpain) which can degrade cytoskeletal structures. Calpain activity and levels will be assayed in different brain regions of numerous animal species using enzymatic assay procedures and antibody binding techniques; the data will then be compared to cell degeneration in the particular areas and to the expected lifespan of the species. Calpain's role in the aging process will then be inferred from these results. In related studies, the activity of lysosomal proteases will also be assayed. Further experiments are designed to examine the distribution and the physiological consequence of lipofuscin or lipofuscin-like dence-body accumulations in the brain. Using morphometric methods, the extent of dense-body accumulation will be related to cell loss, calpain levels, and lysosomal protease activities. In addition, electrophysiological parameters, such as membrane potential and resistance, evoked e.p.s.p. amplitudes, and so forth will be examined in hippocampal neurons containing pharmacologically induced dense-body accumulations. Causal relationships between these various phenomena may be deduced for the collected results.

这个项目的目标是描述生化事件的特征。 在衰老过程中潜在的神经细胞退化。具体的关注焦点 基于两种机制，这可能是相关的。主要的重点是直接 能降解细胞骨架的钙激活的蛋白水解酶(Calain) 结构。将在不同的大脑中检测钙蛋白酶的活性和水平 许多动物物种的区域使用酶分析程序和 抗体结合技术；然后将数据与细胞进行比较 在特定区域的退化和预期寿命 物种。然后，将从以下方面推断CalPain在衰老过程中的作用 这些结果。在相关研究中，溶酶体蛋白酶的活性将 也要做化验。进一步的实验被设计来检验 脂褐素的分布及生理效应 脂褐素样登斯--身体在大脑中蓄积。使用形态测量学 方法，致密小体聚集的程度将与细胞丢失有关， 钙蛋白水平和溶酶体蛋白酶活性。此外, 电生理参数，如膜电位和电阻， 脑电诱发电位。波幅等将在海马区进行检测 含有药物诱导的致密体积聚的神经元。 这些不同现象之间的因果关系可以推断为 收集的结果。