Cognitive Decline & Protein Expression Profiles in Aging

描述（由申请方提供）：本提案旨在评估行为定义动物海马体离散区域中蛋白质表达谱的年龄相关变化。即使没有明显的病理过程，认知功能也会随着年龄的增长而下降。为了分离导致学习和记忆下降的机制，需要研究延迟或逆转与年龄相关的功能下降的干预措施的效果。导致大脑衰老的因素之一是IGF-1。脑中IGF-1随年龄增长而减少;全身给予GHRH或生长激素或中央给予IGF-1可改善突触特征和葡萄糖代谢，逆转NMDAR 2a和2b的年龄相关性下降，并改善认知能力。尽管与脑老化相关的信息很多，但对脑老化的机制以及延缓或逆转脑老化的潜在治疗靶点仍然知之甚少。由于大脑衰老无疑是基于蛋白质表达的改变，我们对大脑衰老的理解需要1）对具有相关行为基础的特定大脑区域的蛋白质表达模式进行彻底分析，2）分析已知影响老年动物认知能力的干预措施后蛋白质表达模式的变化。我们的总体假设是，年龄相关的额叶依赖性和海马依赖性的学习和记忆任务的性能下降的结果从改变前额叶皮层和CA 1，CA 2/3和海马齿状区域内的蛋白质表达谱，分别。具体目标是：1）评估行为定义动物海马相关区域内蛋白质表达谱的年龄相关变化; 2）确定GH/IGF-1替代对这些区域内蛋白质表达谱的影响;和3）评估成人发病GH/IGF-1缺乏的新模型对认知功能和CA 1内蛋白质表达谱的影响，海马CA 2/3区和齿状区。研究将使用二维差异凝胶电泳（2-DIGE）进行蛋白质组规模的蛋白质定量，并使用MALDI-ToF/ToF质谱法进行蛋白质鉴定。这些结果将首次全面调查离散大脑区域中与年龄相关的蛋白质组变化，这些变化导致随着年龄的增长而出现认知缺陷。

DESCRIPTION (provided by applicant): This proposal is designed to assess age-related changes in protein expression profiles in discrete areas of the hippocampus of behaviorally defined animals. Even in the absence of overt pathological processes, cognitive function decreases with age. To isolate the mechanisms that contribute to the decline in learning and memory, studies of the effects of interventions that delay, or reverse the age-related decline in function are required. One of the factors that contributes to brain aging is IGF-1. IGF-1 decreases in the brain with age; systemic administration of GHRH or growth homrone or central administration of IGF-1 improves synaptic profiles and glucose metabolism, reverses the age-related decline in NMDAR2a and 2b and improves cognitive ability. Although much information related to brain aging is known, the mechanisms responsible for brain aging and potential therapeutic targets to delay or reverse brain aging remain poorly understood. Since brain aging is undoubtedly based in alterations in protein expression, advances in our understanding of brain aging require 1) a thorough analysis of protein expression patterns in specific brain regions that have a relevant behavioral basis and 2) analysis of changes in protein expression patterns after interventions known to impact cognitive ability in older animals. Our overall hypothesis is that the age-related decline in frontal lobe-dependent and hippocampally-dependent performance on tasks of learning and memory result from altered protein expression profiles within the prefrontal cortex and CA1, CA2/3 and dentate regions of the hippocampus, respectively. Specific aims are to: 1) Assess age-related changes in protein expression profiles within the relevant regions of the hippocampus in behaviorally defined animals; 2) Determine the effect of GH/IGF-1 replacement on protein expression profiles within these regions; and 3) Assess the effects of a novel model of adult-onset GH/IGF-1 deficiency on cognitive function and protein expression profiles within CA1, CA2/3 and dentate regions of the hippocampus. Studies will use 2-Dimensional Difference in Gel Electrophoresis (2-DIGE) for proteomic scale protein quantification and MALDI-ToF/ToF mass spectrometry for protein identification. The results will provide the first comprehensive investigation of age-related changes in the proteome in discrete brain regions that contributes to cognitive deficits with age.