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: 8127281
• 负责人: Colleen A. Mangold
• 金额: $ 2.78万
• 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/8127281
• 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. PUBLIC HEALTH RELEVANCE: Cognitive decline with aging reduces independence, quality of life, and productivity in older individuals. Although much is known about the mechanisms underlying neurodegenerative diseases such as Alzheimer's and Parkinson's, very little is known concerning the molecular changes that contribute to cognitive decline with age. This project will build upon previous research of synaptic mechanisms of age-associated cognitive decline in the hippocampus. The studies proposed here will examine the hypothesis that miRNA expression changes with aging and/or cognitive decline regulate changes in synaptic protein expression, resulting in decreased neurotransmission efficiency. This research will help elucidate the etiology of cognitive decline and potentially provide targets for the development of new therapies which will increase the cognitive health span for older individuals.

描述（由申请人提供）：随着年龄的增长，认知能力下降会降低老年人的独立性、生活质量和工作效率。虽然比阿尔茨海默氏症和帕金森氏症等神经退行性疾病更常见，但认知能力下降的病因尚不清楚。本研究的中心假设是，随着年龄和认知能力下降，miRNAs的差异表达通过调节蛋白质表达对突触可塑性和认知产生负面影响。我们之前的研究利用Fischer 344 x Brown Norway （F1）大鼠通过Morris水迷宫测试进行认知分层，发现海马mRNA和蛋白表达随年龄和认知能力下降而变化。有趣的是，在比较成年（12个月）和老年（26个月）认知完好的大鼠和老年认知受损的大鼠时，我们发现了一些与神经元可塑性相关的蛋白质表达的变化，这些变化不在转录水平上调节。这表明蛋白质表达调控的替代机制，包括mirna的作用。在使用相同模型和行为测试的试点研究中，我们已经确定了随年龄调节的mirna，以及在认知完好和受损的老年动物之间特异性调节的mirna。这些mirna的预测靶标包括许多我们已经确定下调但转录水平不变的蛋白质。这表明mirna是海马蛋白表达随认知能力下降和衰老变化的调节机制之一。为了扩展我们的初步结果，在第一个特定目标中，将在成年和老年认知分层的Fischer 344 x Brown Norway大鼠的海马CA1， CA2/3和DG亚区测定所有已知大鼠miRNAs的海马表达。这将提供海马miRNA表达与衰老和认知障碍的第一个全基因组检查。差异表达的mirna将通过qPCR确认，潜在的靶点将通过硅分析确定。在目标预测之后，所有miRNA表达和目标数据将与我们现有的关于衰老和认知能力下降的mRNA和蛋白质表达数据集相结合，以确定特定miRNA可能的调节点。第二个特定目标将确定由差异表达的mirna调节的特定蛋白质组。在神经元细胞培养中，受认知能力下降或衰老调控的特定mirna将过度/不足表达，以评估蛋白质表达的特异性和全局变化。直接/间接调控的分化将通过使用被调控基因的3' UTR的报告基因测定来确定。不仅了解受衰老和认知能力下降调控的miRNA，而且了解它们已确认的调控靶点，将有助于了解miRNA表达改变对可塑性和认知的潜在影响。