Mechanisms of Cognitive Decline During Aging

描述(由申请者提供)：提出的是一项富有成效的研究计划的继续，其总体目标是阐明认知能力衰退的机制(S)。为了实现这一目标，我们最初组织并将继续实施一项研究计划，其中包括4个研究项目、3个必要的核心设施和一批有才华的调查人员。这项研究计划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会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将确定目前已确定的与年龄相关的氧化敏感蛋白的作用，以及大多数大脑区域的氧化还原状态在认知能力随年龄下降中的高度显著变化。项目2将确定侮辱诱导的蛋白磷酸盐下降导致一些激酶的持续激活，以及导致AD神经病理和认知功能下降的氧化应激的作用和机制。项目3将确定即刻早期基因产物在认知衰老和中枢神经系统氧化应激过程中控制细胞内钙通道和细胞内钙稳态的潜在机制。项目4将评估重要的卵巢类固醇孕酮增强LTP和减少随年龄增长的认知衰退的信号机制(S)，重点是它对N-甲基-D-天冬氨酸受体的影响。所有这些研究项目都是交互的，它们机械地关注项目的总体假设，共享想法、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中的重要功能读数。这是通过一个行政核心(核心A)实现的，该核心将监督该计划并提供生物统计支持，一个动物资源和行为和评估核心(核心B)将提供对所有动物模型的护理和行为特征描述，以及一个电生理学核心(核心C)将提供对年龄、基因类型、侮辱或干预对记忆和学习的电生理特征LTP的影响的评估。这一机制驱动和统计验证的多学科研究计划，专注于确定认知老化的关键分子和功能机制，将增强我们对氧化应激在认知老化中的作用的理解，并产生有效干预的潜在靶点。

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.