Mechanisms of Cognitive Decline During Aging

描述（由申请人提供）：提议是一个富有成效的研究项目的延续，其总体目标是阐明随着年龄增长认知能力下降的潜在机制。为了实现这一目标，我们最初组织并将继续进行一个研究计划，其中包括4个研究项目，3个基本核心设施和一群有才华的研究人员。该研究项目是由一个现在得到有力支持的假设推动的，即大脑中的氧化应激导致与年龄相关的氧化损伤，是认知衰老速度的主要决定因素。因此，这4个研究项目侧重于对这些问题进行系统评估。项目1将确定现已确定的与年龄相关的氧化敏感蛋白的作用，以及随着年龄增长认知能力下降的大多数大脑区域氧化还原状态的高度显著变化。项目2将确定胰岛素诱导的磷酸蛋白下降导致多种激酶持续激活和氧化应激导致ad神经病理和认知能力下降的作用和机制。项目3将确定在认知老化和中枢神经系统氧化应激过程中控制细胞内Ca2+通道和细胞内Ca2+稳态的即时早期基因产物的功能机制。项目4将评估重要的卵巢类固醇黄体酮增强LTP和减少随年龄增长的认知能力下降的信号机制，重点关注其对NMDA受体的影响。所有这些研究项目都是互动的，因为它们的机制关注于项目的总体假设，分享想法，组织，以及使用侮辱或干预后的行为评估作为所有项目共享和使用的动物模型的重要功能读数。这是通过管理核心（核心A）来实现的，该核心将监督该计划并提供生物统计学支持，动物资源和行为与评估核心（核心B）将为所有动物模型提供护理和行为特征，以及电生理核心（核心C）将评估年龄，基因型，侮辱或干预对记忆和学习电生理特征的影响。这个机制驱动和统计验证的多学科研究项目，专注于确定认知衰老背后的关键分子和功能机制，将增强我们对氧化应激在认知衰老中的作用的理解，并产生有效干预的潜在目标。

DESCRIPTION (provided by applicant): Proposed is a continuation of a productive program of research that has the overall goal of elucidating the mechanism(s) underlying cognitive decline with aging. To achieve this goal, we originally organized and will continue a program of research that includes 4 research projects, 3 essential core facilities and a group of talented investigators. The research program is driven by the now strongly supported hypothesis that oxidative stress in the brain leads to age-related oxidative damage and is a major determinant of the rate of cognitive aging. As such the 4 research projects focus on a systematic assessment of these issues. Project 1 will determine the role of now identified age-related oxidation sensitive proteins and highly significant shifts in the redox state of most brain regions in cognitive decline with age. Project 2 will determine the role of and mechanism by which insult-induced decline in protein phosphates results in persistent activation of a number of kinases, and oxidative stress that leads to AD-neuropathology and cognitive decline. Project 3 will determine the mechanisms underlying the function of immediate early gene products that control intracellular Ca2+ channels and intracellular Ca2+ homeostasis during cognitive aging and oxidative stress in the CNS. Project 4 will assess the signaling mechanism(s) by which the important ovarian steroid, progesterone, enhances LTP and reduces cognitive decline with aging, with a focus on its effects on NMDA receptors. All of these research projects are interactive in their mechanistic focus on the overall hypothesis of the program, the sharing of ideas, tissues, and the use of behavioral assessments following insults or interventions as important functional readouts in animal models shared and employed by all projects. This is achieved through an Administration Core (Core A) that will oversee the program and provide biostatistical support, an Animal Resources and Behavioral and Assessment Core (Core B) that will provide care for and behaviorally characterize all animal models and an Electrophysiology Core (Core C) that will provide assessment of the effects of age, genotypes, insults or interventions on an electrophysiological signature of memory and learning, LTP. This mechanistically driven and statistically-validated, multidisciplinary program of research, that focuses on determining critical molecular and functional mechanisms that underlie cognitive aging, will enhance our understanding of the role of oxidative stress in cognitive aging, and generate potential targets for effective intervention.