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: 9895037
• 负责人: Jungsu Kim
• 金额: $ 39.38万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 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/9895037
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Biochemical; Bioinformatics; Biological; Brain; Clinical; Clinical Data; Code; Cognition; Data; Disease; Down-Regulation; Epigenetic Process; Functional disorder; Funding; Gene Expression Regulation; Genes; Genetic Transcription; 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; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nucleotides; PTEN gene; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Play; Process; Proteins; Publishing; RNA Splicing; Role; Testing; Tissues; Transcript; Transcription Alteration; United States National Institutes of Health; Untranslated RNA; age effect; aging brain; amyloid pathology; base; chromosomal location; differential expression; experimental study; human tissue; improved; in vivo; innovation; insight; insulin signaling; miRNA expression profiling; mouse model; neuropathology; normal aging; novel; novel strategies; prevent; protein aggregation; protein profiling; 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.

项目概要/摘要 越来越多的证据表明，表观遗传变化，包括 microRNA (miRNA) 失调，有助于 衰老、精神疾病和神经退行性疾病。 已经为多种疾病、miRNA 在大脑衰老和阿尔茨海默病中的作用产生了有希望的临床数据 AD 疾病（AD）尚未得到彻底研究。在 AD 发病机制中，胰岛素失调。 Tau 和淀粉样蛋白的异常积累被捕获以引发致病性。 鉴于这些蛋白质聚集在 AD 中的关键作用，调节 tau 的策略 和淀粉样蛋白β正在积极寻求作为治疗方法，我们试图定义其作用。 microRNA (miRNA)，特别是 miR-17-92，在 AD 发病机制中的作用，而不是基于此建立假设。 以前众所周知的蛋白质和概念，我们进行了无偏见的转录组学分析实验 并确定 miR-17-92 是大脑衰老过程中最严重失调的 miRNA。 这一发现与美国国立卫生研究院共同基金基因型组织表达最近一项具有里程碑意义的研究一致 (GTEx) 联盟使用 11 个人脑子区域的数据发现了 miR- 的这种失调。 17-92 的表达可能直接促进衰老过程，因此了解其至关重要。 miR-17-92下降对大脑衰老的功能影响，并尝试恢复其水平以改善衰老效果和 最近越来越多的研究表明 miRNA 失调可能导致多种 AD 发病机制。 神经退行性疾病，包括 AD，我们发现 miR-17-92 调节 tau。 在此应用中，可能通过调节胰岛素信号通路来调节磷酸化和APP表达水平。 我们建议研究 miR-17-92 在认知和阿尔茨海默病中的作用，我们将确定如何进行。 使用新型 AAV Tau 小鼠模型研究 miR-17-92 影响学习记忆以及 AD 相关神经病理学 此外，我们将使用几种创新的体内方法来研究 APP 敲入小鼠模型。 miR-17-92 在 Tau 和 Abeta 代谢中的作用机制。