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

基本信息

批准号：
9980258
负责人：
EDWIN TED G. ABEL
金额：
$ 60.31万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
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/9980258
关键词：
Acute Adult Adverse effects Affect Affinity Chromatography Aging Alzheimer&apos s Disease American Animals Area Behavior Control Behavioral Biochemical Biological Assay Brain region Cell Nucleus Cells Centers for Disease Control and Prevention (U.S.)Chronic Cognition Disorders Cognitive deficits Dementia Development Disease Economic Burden Event FRAP1 gene Foundations Future Gene Expression Gene Expression Regulation Genetic Transcription Genomics Health Health Care Costs Hippocampus (Brain)Impaired cognition Impairment In Situ Individual Learning Maps Mediating Memory Memory impairment Mental disorders Messenger RNA Molecular Molecular Target Neurodegenerative Disorders Nuclear Nuclear RNA Occupational Accidents Pathology Pathway interactions Performance Phosphorylation Plant Roots Post-Translational Protein Processing Process Productivity Protein Biosynthesis Protein Synthesis Inhibition Proteins Public Health RNA RNA Processing RNA Splicing RNA Transport RNA-Binding Proteins Regulation Reporting Research Ribosomes Safety Signal Pathway Signal Transduction Sleep Deprivation Synapses Synaptic plasticity Techniques Technology Teenagers Testing Traffic accidents Transcript Translating Translations Viral age related base cell type cognitive function cognitive performance disorder risk excitatory neuron hippocampal subregions improved in vivo in vivo evaluation insight long term memory memory process negative affect nervous system disorder novel therapeutics overexpression regional difference relating to nervous system resilience therapeutic development therapy development transcriptome sequencing

项目摘要

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.

项目概要睡眠不足对个人健康和公共安全以及经济造成越来越大的威胁由于生产力损失、交通事故、职业事故和医疗费用飙升而造成的负担。受睡眠不足影响的人数急剧增加大约 35% 的美国成年人和高达 70% 的青少年表示睡眠不足。剥夺会导致记忆力和表现的严重损害，加剧精神疾病和神经系统疾病并增加疾病风险，尤其是阿尔茨海默氏症等神经退行性疾病鉴于大量的人受到睡眠不足的影响，并且可能造成毁灭性的后果。睡眠不足对疾病和痴呆的影响，有必要识别细胞睡眠剥夺的后果并确定受影响的具体分子目标和过程。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，尽管睡眠剥夺发挥这些影响的具体机制仍然存在人们对海马体——记忆的关键区域——特别容易受到影响知之甚少。急性睡眠剥夺的影响之前，我们发现睡眠剥夺会降低蛋白质的合成。我们捕捉到了海马体导致突触可塑性受损和缺陷的情况。剥夺针对影响基因表达调节的多个过程，其中包括转录、RNA 加工和定位以及蛋白质合成的变化。建议定义睡眠剥夺影响基因的分子和细胞机制在具体目标 1 中，我们确定了海马内受影响的亚区域和细胞类型。关注睡眠不足影响蛋白质合成从而产生不利影响的信号通路长期记忆和突触可塑性，重点是确定睡眠不足的恢复机制。具体目标 2，我们研究睡眠剥夺对亚细胞水平 RNA 命运的影响明确详细描述了睡眠剥夺对可用于翻译的 mRNA 库的影响。 3、我们采用最先进的技术来定义睡眠不足对各次区域的影响海马体和单个细胞类型内提供详细的空间图和细胞特征我们综合体内行为的综合建议的结果。减轻睡眠剥夺对记忆力影响的操作，对影响的亚细胞分析睡眠剥夺对 RNA 命运和蛋白质合成的影响，以及睡眠细胞特异性特征的识别剥夺，将为睡眠剥夺对记忆的负面影响提供重要的见解，可能会导致治疗方法的开发来抵消睡眠不足的后果认知和神经退行性疾病。