Mechanistic Studies on the Impact of Sleep Deprivation on Gene Regulation

睡眠剥夺对基因调控影响的机制研究

• 批准号: 10286553
• 负责人: EDWIN TED G. ABEL
• 金额: $ 34.47万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286553
• 关键词: Acute; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Bilateral; Brain region; Cause of Death; Cell Nucleus; Cells; Cessation of life; Chronic; Cognition Disorders; Development; Disease Progression; Disease susceptibility; Dorsal; Economic Burden; Exhibits; Family; Foundations; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genetic Translation; Health; Healthcare; Hippocampus (Brain); Human; Impaired cognition; Incidence; Individual; Injections; Investigation; Label; Long-Term Effects; Longevity; Medical; Memory; Messenger RNA; Molecular; Mus; Mutate; Neurodegenerative Disorders; Neurons; Nuclear; Nuclear RNA; Onset of illness; Pathogenesis; Pathologic; Pathology; Phenotype; Polyribosomes; Predisposition; Process; Proteins; Public Health; RNA; RNA Processing; RNA Splicing; RNA-Binding Proteins; Regulation; Research; Resolution; RiboTag; Ribosomal Proteins; Ribosomes; Risk; Science; Sleep; Sleep Deprivation; Sleep disturbances; Societies; Symptoms; Tauopathies; Techniques; Technology; Teenagers; Therapeutic; Translating; Translations; United States; Viral; Wild Type Mouse; care burden; cell type; deprivation; disease phenotype; emerging adult; excitatory neuron; experimental study; genome-wide; genome-wide analysis; insight; mRNA Expression; mRNA sequencing; mouse model; novel; novel therapeutics; parent grant; poor sleep; relating to nervous system; response; sleep pattern; tau Proteins; tau-1; transcriptome; transcriptome sequencing; translatome; young adult

Project Summary/Abstract Alzheimer's disease is now considered by some experts to be the third leading cause of death in the United States, inflicting enormous health care and economic burdens on individuals, families and society. With advances in medical science and technology substantially extending human lifespan, the numbers of individuals living longer and affected by Alzheimer's disease and related dementias is expected to increase significantly. While sleep disturbances have long been viewed as symptoms of Alzheimer's disease and other neurodegenerative diseases, recent research has suggested that chronic sleep disruption may be a significant risk factor for Alzheimer's disease decades later. Poor sleep patterns and chronic sleep loss also appear to accelerate the rate of disease progression and pathogenesis. Acute and chronic sleep deprivation have also been shown to increase tau pathologies and amyloid beta peptides, pathological hallmarks of Alzheimer's disease. Recent estimates suggest that over 35% of adults suffer from chronic sleep deprivation making it imperative that we identify the mechanisms through which chronic sleep deprivation affects Alzheimer's pathogenesis. The hippocampus, a critical brain region for memory, is particularly susceptible to the effects of sleep deprivation and is one of the first regions to exhibit phenotypic pathologies in Alzheimer's disease. We hypothesize that chronic sleep deprivation causes aberrant nuclear RNA splicing and processing, and limits the available pool of mRNA for translation to affect gene expression in tau pathogenesis. The objective of this Alzheimer's disease Supplement proposal is to identify the impact of chronic sleep deprivation on neuronal mRNA processing in the nucleus and to define the translatome of excitatory neurons in the hippocampus in a mouse model of tauopathy related to Alzheimer's disease and related dementias. We will use deep neuronal nuclear RNA sequencing to identify the impact of chronic sleep deprivation on mRNA processing and splicing, and an advanced viral RiboTag strategy to specifically target excitatory neurons in the hippocampus followed by deep RNA sequencing of the mRNA associated with translating polyribosomes in a mouse model for tauopathies related to Alzheimer's disease. The results from our multi-level experiments defining genome-wide impacts of chronic sleep deprivation with cell-type specific resolution on RNA processing, and the identification of a cell-type specific translatome signature of chronic sleep deprivation, will provide significant insights into the negative impacts of sleep deprivation on tau pathogenesis related to Alzheimer's disease, potentially leading to the development of novel therapeutics to counteract the consequences of sleep loss on cognition and neurodegenerative disorders.

项目摘要/摘要 现在，一些专家认为阿尔茨海默氏病是曼联的第三大死亡原因 国家，给个人，家庭和社会带来巨大的医疗保健和经济负担。和 医学和技术的进步大大延长了人类的寿命， 预计患有长期和受阿尔茨海默氏病影响的人会增加 显著地。长期以来，睡眠障碍一直被视为阿尔茨海默氏病和其他的症状 神经退行性疾病，最近的研究表明，慢性睡眠破坏可能是重要的 几十年后，阿尔茨海默氏病的危险因素。睡眠模式不良和慢性睡眠丧失似乎也 加速疾病进展和发病机理的速度。急性和慢性睡眠剥夺也有 被证明可以增加tau病理和淀粉样β肽，阿尔茨海默氏症的病理标志 疾病。最近的估计表明，超过35％的成年人患有慢性睡眠剥夺使其 我们必须确定慢性睡眠剥夺影响阿尔茨海默氏症的机制 发病。海马是一种记忆的关键大脑区域，特别容易受到影响 睡眠不足，是在阿尔茨海默氏病中表现出表型病理的最早地区之一。我们 假设慢性睡眠剥夺会导致异常的核RNA剪接和处理，并限制 可用的mRNA库翻译以影响tau发病机理中的基因表达。这个目的 阿尔茨海默氏病补充提案是确定慢性睡眠剥夺对 核中的神经元mRNA处理，并定义兴奋性神经元的翻译组 与阿尔茨海默氏病和相关痴呆症相关的小鼠tauopathy小鼠模型中的海马。我们 将使用深层神经元核RNA测序来确定慢性睡眠剥夺对mRNA的影响 加工和剪接，以及一种高级病毒核糖策略，以专门针对兴奋性神经元 海马，然后进行与在A中翻译多核糖体相关的mRNA的深度RNA测序 与阿尔茨海默氏病有关的小鼠模型。我们多级实验的结果 用细胞类型的分辨率定义慢性睡眠剥夺对RNA的慢性睡眠剥夺的影响 处理，以及鉴定细胞类型的特定翻译体剥夺的特异性翻译体特征，将 对睡眠剥夺对与tau发病机理的负面影响提供了重大见解 阿尔茨海默氏病，有可能导致新的疗法发展以抵消 睡眠丧失对认知和神经退行性疾病的后果。