Mechanisms of Cognitive Decline During Aging

衰老过程中认知能力下降的机制

• 批准号: 7118151
• 负责人: JAMES W. SIMPKINS
• 金额: $ 157.15万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7118151
• 关键词: aging; cognition disorders

DESCRIPTION (provided by applicant): The present program project has the overall goal of elucidating the mechanism(s) underlying cognitive decline with aging. To achieve this goal, we have organized a program of research that includes 4 research projects, three 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. An essential approach to this problem is to define the animal-to-animal variability in cognitive aging, relate these inter-animal differences to oxidative damage in specific brain regions and to determine the signaling pathways that communicate oxidative events to cellular responses. As such, the four research projects focus on a systematic assessment of these issues. Project 1 will define the rate and inter-animal differences in cognitive and psychomotor aging in C57BL/6 mice and define the relationship between these behaviors and regional, cellular, subcellular and molecular oxidative damage in the brain as well as the ability of caloric restriction to affect these events. Project 2 will determine the mechanism by which estrogens attenuate the activation of NFKB, a major oxidative signaling pathway, and thereby reduce neuronal vulnerability during aging. Project 3 will determine the effects of cognitive aging and oxidative stress on intracellular Ca 2+ channels, their associated signaling proteins and the resulting effects on intracellular Ca 2+ homeostasis. Project 4 will assess the other important ovarian steroid, progesterone, for its effects on cognitive aging and brain health, based upon preliminary data that indicate that progesterone is a potent inhibitor of the GABAA receptor and a potent neuroprotectant. All of these research projects are interactive in the sharing of ideas, tissues, and the use of behaviorally characterized mice that are distributed to projects based upon their presentation of the behavioral diversity of the population as a whole. This is achieved through an Administrative Core (Core A) that will oversee the program, a Animal Care Behavioral and Assessment Core (Core B) that will provide care for and behavioral characterization of all mice and a Biostatistics Core (Core C) that will provide statistical design, animal randomization and analysis of all data generated. This statistically based, multidisciplinary program of research, aimed at the characterization of cognitive aging, will enhance our understanding of the role of oxidative stress in cognitive aging, the mechanisms mediating these effects and potential targets for effective intervention.

描述（由申请人提供）：本项目的总体目标是阐明衰老导致认知能力下降的机制。为了实现这一目标，我们组织了一项研究计划，其中包括 4 个研究项目、三个重要的核心设施和一群才华横溢的研究人员。该研究计划是由目前得到强有力支持的假设驱动的，即大脑中的氧化应激会导致与年龄相关的氧化损伤，并且是认知衰老速度的主要决定因素。 解决这个问题的一个重要方法是定义动物间认知衰老的变异性，将这些动物间差异与特定大脑区域的氧化损伤联系起来，并确定将氧化事件传达给细胞反应的信号通路。因此，这四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 C57BL/6 小鼠认知和精神运动衰老的速率和动物间差异，并确定这些行为与大脑中区域、细胞、亚细胞和分子氧化损伤之间的关系，以及热量限制影响这些事件的能力。 项目 2 将确定雌激素减弱 NFKB（一种主要氧化信号通路）激活的机制，从而减少衰老过程中神经元的脆弱性。项目 3 将确定认知衰老和氧化应激对细胞内 Ca 2+ 通道、其相关信号蛋白的影响以及由此产生的对细胞内 Ca 2+ 稳态的影响。项目 4 将评估另一种重要的卵巢类固醇黄体酮对认知衰老和大脑健康的影响，初步数据表明黄体酮是 GABAA 受体的有效抑制剂和有效的神经保护剂。所有这些研究项目在共享想法、组织和使用行为特征小鼠方面都是互动的，这些小鼠根据其对整个群体行为多样性的呈现而分配给项目。 这是通过监督该计划的管理核心（核心 A）、为所有小鼠提供护理和行为特征的动物护理行为和评估核心（核心 B）以及提供统计设计、动物随机化和对生成的所有数据进行分析的生物统计核心（核心 C）来实现的。这项基于统计的多学科研究计划旨在表征认知衰老，将增强我们对氧化应激在认知衰老中的作用、介导这些影响的机制以及有效干预的潜在目标的理解。