Differentially expressed hippocampal miRNAs with age and cognitive decline

海马 miRNA 随年龄和认知能力下降而差异表达

• 批准号: 8366204
• 负责人: Colleen A. Mangold
• 金额: $ 2.83万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2014-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8366204
• 关键词: 3' Untranslated Regions; Adult; Affect; Age; Age-Months; Age-associated memory impairment; Aging; Algorithms; Alzheimer' s Disease; Animals; Behavior; Binding; Biochemistry; Bioinformatics; Biological Assay; Cell Culture Techniques; Cognition; Cognitive; Cognitive aging; Cognitive deficits; Complement; Computer Simulation; Data; Data Set; Databases; Development; Elderly; Elements; Etiology; Genes; Global Change; Health; Hippocampus (Brain); Hybrids; Immunoblotting; Impaired cognition; In Vitro; Individual; Learning; Maintenance; Memory; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Biology; Molecular Profiling; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Neurosciences; Norway; Outcome; Parkinson Disease; Performance; Phenotype; Pilot Projects; Play; Population; Productivity; Proteins; Proteomics; Quality of life; Rattus; Rattus norvegicus; Regulation; Reporter; Research; Role; Scientist; Set protein; Synapses; Synaptic plasticity; System; Testing; Training Programs; Transcript; Work; aged; base; behavior test; cognitive function; design; experience; genome-wide; hippocampal subregions; insight; mRNA Expression; morris water maze; multidisciplinary; neurotransmission; novel; protein expression; response

DESCRIPTION (provided by applicant): Cognitive decline with aging reduces independence, quality of life, and productivity in older individuals. While much more common than neurodegenerative diseases, such as Alzheimer's and Parkinson's, the etiology of cognitive decline remains unknown. The central hypothesis of this proposed study is that differential expression of miRNAs with age and cognitive decline negatively impacts synaptic plasticity and cognition through the regulation of protein expression. Our previous studies have identified hippocampal mRNA and protein expression changes with aging and cognitive decline utilizing Fischer 344 x Brown Norway (F1) rats cognitively stratified by Morris Water Maze testing. Interestingly, in comparisons of Adult (12 month) and Aged (26 Month) Cognitively Intact, and Aged Cognitively Impaired rats we have identified a number of changes in protein expression related to neuronal plasticity that are not regulated at the transcript level. This suggests a role for alternate mechanisms of protein expression regulation, including miRNAs. In pilot studies using the same model and behavioral testing we have identified miRNAs regulated with age and miRNAs specifically regulated between cognitively intact and impaired aged animals. The predicted targets of these miRNAs included many of those proteins that we have identified as down regulated but whose transcript levels are unchanged. This suggests a role for miRNAs as one of the regulatory mechanisms underlying the hippocampal protein expression changes with cognitive decline and aging. To expand on our preliminary results, in the first specific aim, hippocampal expression of all known rat miRNAs will be determined in CA1, CA2/3 and DG hippocampal sub regions of Adult and Aged cognitively stratified Fischer 344 x Brown Norway rats. This will provide the first genome-wide examination of hippocampal miRNA expression with aging and cognitive impairment. Differentially expressed miRNAs will be confirmed by qPCR and potential targets will be determined by in silico analysis. Following target prediction, all miRNA expression and target data will be integrated with our existing mRNA and protein expression datasets on aging and cognitive decline to identify likely points of regulation by specific miRNAs. The second specific aim will determine specific sets of proteins regulated by differentially expressed miRNAs. Specific miRNAs regulated with cognitive decline or aging will be over/under-expressed in neuron cell culture to assess both specific and global changes in protein expression. Differentiation of direct/indirect regulation will be determined through reporter assays using the 3' UTR of regulated genes. Knowing not only the miRNAs regulated with aging and cognitive decline but their confirmed regulatory targets will allow for an understanding of the potential outcome of altered miRNA expression on plasticity and cognition.

描述（由申请人提供）：衰老的认知能力下降会降低独立性，生活质量和老年人的生产力。尽管阿尔茨海默氏症和帕金森氏症等神经退行性疾病比神经退行性疾病更为普遍，但认知下降的病因仍然未知。这项拟议的研究的中心假设是，随着年龄的增长，miRNA的差异表达和认知下降通过调节蛋白质表达对突触可塑性和认知产生负面影响。我们以前的研究已经确定了海马mRNA和蛋白质表达的变化，利用Fischer 344 x棕色挪威（F1）大鼠通过Morris Water Maze测试认知分层，随着衰老和认知下降的变化。有趣的是，在比较成人（12个月）和老年（26个月）的认知完整和老年认知受损的大鼠中，我们已经确定了与神经元可塑性相关的蛋白质表达的许多变化，这些变化在转录水平上不受调节。这表明了包括miRNA在内的蛋白质表达调节的替代机制的作用。在使用相同模型和行为测试的试点研究中，我们已经确定了对年龄和miRNA调节的miRNA，在认知完整和衰老动物受损之间受到了特异性调节。这些miRNA的预测靶标包括我们已确定为下调但其转录水平不变的许多蛋白质。这表明miRNA是海马蛋白表达的基础机制之一，随着认知能力下降和衰老的变化。 为了扩展我们的初步结果，在第一个特定目的中，将在CA1，CA2/3和DG海马中确定所有已知大鼠miRNA的海马表达，成人和老年认知上分层的Fischer 344 x棕色挪威大鼠。这将提供对海马miRNA表达的首次基因组检查，并具有衰老和认知障碍。差异表达的miRNA将由qPCR确认，潜在靶标将通过计算机分析确定。按照目标预测，所有miRNA表达和靶数据将与我们现有的mRNA和蛋白质表达数据集集成到衰老和认知能力下降，以确定特定miRNA的可能调节点。 第二个特定目的将确定由差异表达的miRNA调节的特定蛋白质集。在神经元细胞培养中，受认知下降或衰老调节的特异性miRNA将过高/表达不足，以评估蛋白质表达的特定和全球变化。直接/间接调节的分化将通过使用调节基因的3'UTR来确定。不仅了解受衰老和认知下降调节的miRNA，而且他们确认的调节目标还可以理解miRNA表达在可塑性和认知方面改变的潜在结果。