Mechanistic Studies on the Impact of Sleep Deprivation on Gene Regulation

项目摘要 睡眠不足对个人健康和公共安全构成越来越大的威胁，并对经济造成 由于生产力下降、交通事故、职业事故和医疗成本飞涨造成的负担。 受睡眠剥夺影响的人数出现了惊人的增长 大约35%的美国成年人和令人震惊的70%的青少年报告睡眠不足。沉睡 剥夺会导致严重的记忆和表现障碍，加重精神和精神障碍 神经紊乱并增加疾病风险，特别是阿尔茨海默氏症等神经退行性疾病 疾病。考虑到受睡眠剥夺影响的人数之多，以及潜在的破坏性 睡眠不足的后果在疾病和痴呆症方面，至关重要的是识别细胞 睡眠剥夺的后果，并确定特定的分子靶点和过程受到影响。 最近的研究表明，急性睡眠剥夺对记忆的影响发生在细胞和 突触水平，尽管睡眠剥夺产生这些影响的具体机制仍然存在 人们对此知之甚少。海马体是大脑记忆的关键区域，特别容易受到 急性睡眠剥夺的影响。此前，我们发现睡眠不足会减少大脑中蛋白质的合成 海马体导致突触可塑性的损害和缺陷。我们假设睡眠 剥夺针对影响基因表达调控的多个过程，基因表达调控包括 转录、RNA加工和定位以及蛋白质合成的变化。这样做的目的是 建议定义睡眠剥夺影响基因的分子和细胞机制 并确定海马区内受影响的亚区和细胞类型。在具体目标1中，我们 关注睡眠剥夺影响蛋白质合成从而产生负面影响的信号通路 长期记忆和突触可塑性，重点是识别对睡眠丧失的弹性机制。在……里面 具体目标2，我们研究了睡眠剥夺对RNA命运的亚细胞水平和 明确详述睡眠不足对可供翻译的信使核糖核酸池的影响。以特定的目标 3，我们使用最先进的技术来定义睡眠剥夺在不同区域的影响 海马体和单个细胞类型内提供了详细的空间地图和细胞签名 睡眠不足的影响。我们的综合方案整合了体内行为的结果 减轻睡眠剥夺对记忆影响的操作，亚细胞分析的影响 睡眠剥夺对RNA命运和蛋白质合成的影响以及睡眠细胞特异性信号的识别 剥夺，将提供对睡眠剥夺对记忆的负面影响的重要见解， 潜在地导致了治疗方法的发展，以抵消睡眠不足的后果 认知和神经退行性疾病。

Project Summary Sleep deprivation presents an increasing threat to individual health and public safety as well as an economic burden due to lost productivity, traffic accidents, occupational accidents, and skyrocketing healthcare costs. There has been an astonishing rise in the number of individuals affected by sleep deprivation with approximately 35% of U.S. adults and a staggering 70% of teenagers reporting insufficient sleep. Sleep deprivation induces significant impairments in memory and performance, aggravates psychiatric and neurological disorders and increases disease risk, especially neurodegenerative disorders such as Alzheimer’s disease. Given the significant number of people affected by sleep deprivation, and the potentially devastating consequences of sleep loss in terms of disease and dementia, it is essential to identify the cellular consequences of sleep deprivation and to define the specific molecular targets and processes impacted. Recent research suggests that the influence of acute sleep deprivation on memory occurs at the cellular and synaptic level, although the specific mechanisms through which sleep deprivation exerts these effects remain poorly understood. The hippocampus, a critical brain region for memory, is particularly susceptible to the effects of acute sleep deprivation. Previously, we found that sleep deprivation decreases protein synthesis in the hippocampus leading to impairments and deficits in synaptic plasticity. We hypothesize that sleep deprivation targets multiple processes that affect the regulation of gene expression, which is comprised of changes in transcription, RNA processing and localization, and protein synthesis. The objectives of this proposal are to define the molecular and cellular mechanisms through which sleep deprivation impacts gene regulation and to define the affected subregions and cell types within the hippocampus. In Specific Aim 1, we focus on the signaling pathways through which sleep deprivation affects protein synthesis to adversely impact long-term memory and synaptic plasticity with a focus on identifying mechanisms of resilience to sleep loss. In Specific Aim 2, we investigate the effects of sleep deprivation on RNA fate at the subcellular level and explicitly detail the effects of sleep deprivation on the pool of mRNA available for translation. In Specific Aim 3, we employ state of the art techniques to define the impact of sleep deprivation across subregions within the hippocampus and within individual cell types providing a detailed spatial map and cellular signature of the effects of sleep deprivation. The results from our comprehensive proposal integrating in vivo behavioral manipulations to mitigate the effects of sleep deprivation on memory, the subcellular analysis of the effects of sleep deprivation on RNA fate and protein synthesis, and the identification of cell specific signatures of sleep deprivation, will provide significant insights into the negative impacts of sleep deprivation on memory, potentially leading to the development of therapeutics to counteract the consequences of sleep loss on cognition and neurodegenerative disorders.