The role of aging-associated microRNAs in Alzheimer's disease

衰老相关的 microRNA 在阿尔茨海默病中的作用

• 批准号: 9195378
• 负责人: Jungsu Kim
• 金额: $ 39.13万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9195378
• 关键词: Address; Affect; Age; Aging; Aging-Related Process; Alzheimer' s Disease; Amyloid beta-Protein; Biochemical; Bioinformatics; Biological; Brain; Clinical Data; Code; Cognition; Data; Disease; Down-Regulation; Epigenetic Process; Figs - dietary; Functional disorder; Funding; Gene Expression Regulation; Gene Targeting; Genes; Genotype; Human; Individual; Insulin Signaling Pathway; Knock-in Mouse; Lead; Learning; Length; Link; LoxP-flanked allele; Maps; Mediating; Memory; Memory Loss; Memory impairment; Mental disorders; Messenger RNA; Metabolism; Methods; MicroRNAs; Molecular; Molecular Profiling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nucleotides; PTEN gene; Pathogenesis; Pathology; Pathway interactions; Play; Proteins; Publishing; RNA Splicing; Role; Staging; Testing; Tissues; Transcript; United States National Institutes of Health; Untranslated RNA; age effect; aging brain; amyloid pathology; base; chromosomal location; differential expression; human tissue; improved; in vivo; innovation; insight; insulin signaling; mouse model; neuropathology; normal aging; novel; novel strategies; prevent; protein aggregation; protein profiling; research study; tau Proteins; tau aggregation; tau phosphorylation; transcription factor; transcriptomics

PROJECT SUMMARY/ABSTRACT Mounting evidence suggests that epigenetic changes, including microRNA (miRNA) dysregulation, contribute to aging, psychiatric disorders and neurodegenerative disorders. Although modulations of miRNA function have generated promising clinical data for several diseases, miRNA’s roles in brain aging and Alzheimer’s disease (AD) have not been investigated thoroughly. During AD pathogenesis, dysregulation of insulin signaling is evident. Abnormal accumulation of Tau and amyloid beta is hypothesized to initiate a pathogenic cascade leading to AD. Given the critical role of these protein aggregations in AD, strategies to modulate tau and amyloid beta are actively being pursued as therapies. Toward that end, we seek to define the role of microRNAs (miRNAs), specifically miR-17-92, in AD pathogenesis. Instead of setting up a hypothesis based on the previously well-known proteins and concepts, we performed unbiased transcriptomics profiling experiments and identified miR-17-92 as the most strongly dysregulated miRNAs during brain aging. Remarkably, our finding is consistent with a recent landmark study by the NIH Common Fund’s Genotype-Tissue Expression (GTEx) consortium’s data using 11 human brain subregions. We hypothesize that such dysregulation of miR- 17-92 expression may directly contribute to aging process. Therefore, it will be critical to understand the functional effect of miR-17-92 decline on brain aging and try to restore its levels to ameliorate aging effect and AD pathogenesis. Mounting studies recently suggests that miRNA dysregulation may contribute to several neurodegenerative disorders, including AD. Interestingly, we found that miR-17-92 regulates tau phosphorylation and APP expression level possibly by modulating insulin signaling pathway. In this application, we propose to investigate the role of miR-17-92 in cognition and Alzheimer’s disease. We will determine how miR-17-92 affects learning and memory and AD-related neuropathology using novel AAV Tau mouse model and APP knock-in mouse model. Furthermore using several innovative in vivo methods, we will investigate the mechanism underlying the role of miR-17-92 in Tau and Abeta metabolism.

项目摘要/摘要 越来越多的证据表明，包括microRNA（miRNA）失调在内的表观遗传变化有助于 衰老，精神疾病和神经退行性疾病。虽然miRNA功能的调制 已经为多种疾病产生了承诺临床数据，miRNA在大脑衰老中的作用和阿尔茨海默氏症的角色 疾病（AD）尚未进行彻底研究。在AD发病机理期间，胰岛素失调 信号是证据。假设TAU和淀粉样蛋白β的异常积累以启动致病性 级联导致广告。鉴于这些蛋白质聚集在AD中的关键作用，因此调节tau的策略 和淀粉样蛋白β正在积极地作为疗法。为此，我们试图定义 MicroRNA（miRNA），特别是miR-17-92，在AD发病机理中。而不是基于 以前众所周知的蛋白质和概念，我们进行了无偏的转录组学分析实验 并确定miR-17-92是大脑衰老过程中最强烈的miRNA。值得注意的是，我们的 发现与NIH Common基金的基因型 - 组织表达的最近具有里程碑意义的研究一致 （GTEX）使用11个人脑子区域的财团数据。我们假设miR-的这种失调 17-92表达可能直接有助于衰老过程。因此，了解 miR-17-92下降对脑衰老的功能作用，并尝试恢复其水平以改善衰老效应和 AD发病机理。越来越多的研究最近表明miRNA失调可能有助于几个 神经退行性疾病，包括AD。有趣的是，我们发现miR-17-92调节tau 通过调节胰岛素信号通路，磷酸化和APP表达水平可能。在此应用程序中 我们建议研究miR-17-92在认知和阿尔茨海默氏病中的作用。我们将确定如何 miR-17-92使用新型AAV TAU鼠标模型影响学习和记忆以及与广告相关的神经病理学 和APP敲入鼠标模型。此外，使用几种创新的体内方法，我们将研究 miR-17-92在tau和Abeta代谢中作用的机制。