Mechanisms of Cognitive Decline During Aging

衰老过程中认知能力下降的机制

• 批准号: 8431378
• 负责人: JAMES W. SIMPKINS
• 金额: $ 146.96万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431378
• 关键词: Age; Aging; Animal Model; Behavior assessment; Brain; Brain region; Caring; Cognitive aging; Core Facility; Electrophysiology (science); Genotype; Goals; Homeostasis; Immediate-Early Genes; Impaired cognition; Intervention; Learning; Memory; Molecular; N-Methyl-D-Aspartate Receptors; Ovarian; Oxidation-Reduction; Oxidative Stress; Phosphotransferases; Progesterone; Proteins; Research; Research Personnel; Research Project Grants; Role; Signal Transduction; Steroids; Tissues; age effect; age related; animal resource; effective intervention; inorganic phosphate; multidisciplinary; neuropathology; oxidation; oxidative damage; programs

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.

描述（由申请人提供）：提出的是一个富有成效的研究计划的延续，其总体目标是阐明随着年龄增长认知能力下降的机制。为了实现这一目标，我们最初组织并将继续一项研究计划，其中包括4个研究项目，3个必要的核心设施和一组有才华的研究人员。该研究计划是由现在强烈支持的假设驱动的，即大脑中的氧化应激导致与年龄相关的氧化损伤，并且是认知老化速度的主要决定因素。因此，4个研究项目侧重于对这些问题进行系统评估。项目1将确定现在确定的与年龄相关的氧化敏感蛋白的作用，以及随着年龄的增长，大多数大脑区域的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蛋白磷酸盐下降导致许多激酶持续激活的作用和机制，以及导致AD神经病理学和认知能力下降的氧化应激。项目3将确定在认知老化和CNS氧化应激过程中控制细胞内Ca2+通道和细胞内Ca2+稳态的即刻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孕酮增强LTP并减少认知能力随年龄增长而下降的信号传导机制，重点是其对NMDA受体的影响。所有这些研究项目都是互动的，其机制集中在程序的整体假设，思想，组织的共享，以及在侮辱或干预后使用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），将监督该计划并提供生物统计支持，动物资源和行为和评估核心（核心B），将提供护理和行为表征所有动物模型和电生理核心（核心C），将提供年龄，基因型，侮辱或干预对记忆和学习的电生理特征的影响的评估来实现的。LTP这种机械驱动和生物学验证的多学科研究计划，重点是确定认知老化的关键分子和功能机制，将提高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目标。

项目成果

Non-feminizing estrogens: a novel neuroprotective therapy.

• DOI: 10.1016/j.mce.2013.12.017
• 发表时间: 2014-05-25
• 期刊: Molecular and cellular endocrinology
• 影响因子: 4.1
• 作者: Petrone AB;Gatson JW;Simpkins JW;Reed MN
• 通讯作者: Reed MN

Novel pharmacotherapy: NNI-362, an allosteric p70S6 kinase stimulator, reverses cognitive and neural regenerative deficits in models of aging and disease.

• DOI: 10.1186/s13287-020-02126-3
• 发表时间: 2021-01-13
• 期刊: Stem cell research & therapy
• 影响因子: 7.5
• 作者: Sumien N;Wells MS;Sidhu A;Wong JM;Forster MJ;Zheng QX;Kelleher-Andersson JA
• 通讯作者: Kelleher-Andersson JA

Chemical probes for analysis of carbonylated proteins: a review.

• DOI: 10.1016/j.jchromb.2010.08.004
• 发表时间: 2011-05-15
• 期刊: JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
• 影响因子: 3
• 作者: Yan, Liang-Jun;Forster, Michael J.
• 通讯作者: Forster, Michael J.

Does phytoestrogen supplementation affect cognition differentially in males and females?

补充植物雌激素对男性和女性认知的影响是否存在差异？

• DOI: 10.1016/j.brainres.2013.02.013
• 发表时间: 2013
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Sumien,Nathalie;Chaudhari,Kiran;Sidhu,Akram;Forster,MichaelJ
• 通讯作者: Forster,MichaelJ

Non-genomic mechanisms of progesterone action in the brain.

• DOI: 10.3389/fnins.2013.00159
• 发表时间: 2013-09-19
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Singh M;Su C;Ng S
• 通讯作者: Ng S