Mechanistic Studies on the Impact of Sleep Deprivation on Gene Regulation

项目总结/摘要 阿尔茨海默氏病现在被一些专家认为是美国第三大死亡原因。 这给个人、家庭和社会造成了巨大的保健和经济负担。与 医学科学和技术的进步大大延长了人类的寿命， 预计寿命更长、受阿尔茨海默病和相关痴呆症影响的人将增加 显著虽然睡眠障碍一直被视为阿尔茨海默病和其他疾病的症状， 神经退行性疾病，最近的研究表明，慢性睡眠中断可能是一个显着的， 几十年后阿尔茨海默病的危险因素。睡眠模式不佳和长期睡眠不足似乎也会 加速疾病进展和发病的速度。急性和慢性睡眠剥夺也 已被证明增加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， 我们必须确定慢性睡眠剥夺影响阿尔茨海默氏症的机制， 发病机制海马体是大脑中记忆的关键区域， 睡眠剥夺，是阿尔茨海默病中最早表现出表型病理的区域之一。我们 假设慢性睡眠剥夺导致异常的核RNA剪接和加工， 可用于翻译以影响tau发病机制中基因表达的mRNA库。的目的 老年痴呆症补充建议是确定慢性睡眠剥夺的影响， 神经元mRNA在细胞核中的加工，并确定兴奋性神经元的翻译组， 在与阿尔茨海默病和相关痴呆相关的tau蛋白病的小鼠模型中，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，以及一种先进的病毒RiboTag策略，专门针对兴奋性神经元， 海马，然后对与翻译多核糖体相关的mRNA进行深度RNA测序， 与阿尔茨海默病相关的tau蛋白病的小鼠模型。我们多水平实验的结果 用RNA细胞类型特异性分辨率确定慢性睡眠剥夺的全基因组影响 处理和识别慢性睡眠剥夺的细胞类型特异性翻译组签名，将 提供了关于睡眠剥夺对tau发病机制的负面影响的重要见解， 阿尔茨海默病，可能导致新的治疗方法的发展，以抵消 睡眠不足对认知和神经退行性疾病的后果。

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.