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、生活质量和生产力。虽然认知能力下降比阿尔茨海默氏症和帕金森氏症等神经退行性疾病更为常见，但其病因仍不清楚。这项研究的中心假设是，随着年龄和认知能力下降，miRNA 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通过莫里斯水迷宫测试进行认知分层的 Fischer 344 x Brown挪威 (F1) 大鼠，确定了海马 mRNA 和蛋白质表达随着衰老和认知能力下降而变化。有趣的是，在对成年（12 个月）和老年（26 个月）认知完整和老年认知障碍大鼠的比较中，我们发现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。这表明蛋白质表达调节的替代机制（包括 miRNA）发挥着作用。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，以及在认知完整和受损的老年动物之间专门调节的 miRNA。这些 miRNA 的预测靶标包括许多我们已确定下调但转录水平未改变的蛋白质。这表明 miRNA 作为海马蛋白表达随认知能力下降和衰老而变化的调节机制之一。 为了扩展我们的初步结果，在第一个具体目标中，将在成年和老年认知分层 Fischer 344 x Brown挪威大鼠的 CA1、CA2/3 和 DG 海马亚区域中测定所有已知大鼠 miRNA 的海马表达。这将首次对海马 miRNA 表达与衰老和认知障碍的关系进行全基因组检查。差异表达的 miRNA 将通过 qPCR 进行确认，并通过计算机分析确定潜在的靶标。在目标预测之后，所有 miRNA 表达和目标数据将与我们现有的有关衰老和认知衰退的 mRNA 和蛋白质表达数据集整合，以识别特定 miRNA 可能的调节点。 第二个具体目标是确定受差异表达 miRNA 调节的特定蛋白质组。受认知衰退或衰老调节的特定 miRNA 将在神经元细胞培养物中过度/表达不足，以评估蛋白质表达的特定和整体变化。直接/间接调节的差异将通过使用调节基因的 3' UTR 的报告分析来确定。不仅了解随着衰老和认知能力下降而调节的 miRNA，而且还了解其已确认的调节目标，将有助于了解 miRNA 表达改变对可塑性和认知的潜在结果。 公共卫生相关性：随着年龄的增长认知能力下降会降低老年人的独立性、生活质量和生产力。尽管人们对阿尔茨海默氏症和帕金森氏症等神经退行性疾病的潜在机制了解很多，但对于导致认知能力随年龄下降的分子变化却知之甚少。该项目将建立在先前对海马体中与年龄相关的认知衰退的突触机制的研究的基础上。这里提出的研究将检验这样的假设：miRNA 表达随着衰老和/或认知能力下降而变化，调节突触蛋白表达的变化，从而导致神经传递效率下降。这项研究将有助于阐明认知能力下降的病因，并有可能为开发新疗法提供目标，从而延长老年人的认知健康寿命。