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：
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
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/10286553
关键词：
Acute Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos 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

项目摘要

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.

项目概要/摘要阿尔茨海默病现在被一些专家认为是美国第三大死因国家，给个人、家庭和社会造成巨大的医疗保健和经济负担。和医学科学技术的进步大大延长了人类的寿命预计寿命更长且受阿尔茨海默病和相关痴呆症影响的人数将会增加显著地。虽然睡眠障碍长期以来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重要的原因几十年后阿尔茨海默病的危险因素。不良的睡眠模式和慢性睡眠不足似乎也会加速疾病进展和发病的速度。急性和慢性睡眠不足也已被证明可增加 tau 病理学和淀粉样β肽（阿尔茨海默病的病理标志）疾病。最近的估计表明，超过 35% 的成年人患有慢性睡眠不足，这使得我们必须确定长期睡眠不足影响阿尔茨海默病的机制发病。海马体是记忆的关键大脑区域，特别容易受到以下因素的影响：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。我们假设长期睡眠不足会导致核 RNA 剪接和加工异常，并限制用于翻译以影响 tau 发病机制中基因表达的可用 mRNA 库。此举的目的阿尔茨海默病补充提案旨在确定长期睡眠不足对睡眠的影响细胞核中神经元 mRNA 的加工，并定义细胞核中兴奋性神经元的翻译组与阿尔茨海默病和相关痴呆症相关的 tau 蛋白病小鼠模型中的海马体。我们将使用深度神经元核 RNA 测序来确定长期睡眠剥夺对 mRNA 的影响处理和剪接，以及先进的病毒 RiboTag 策略，专门针对神经元中的兴奋性神经元海马体，然后对与翻译多核糖体相关的 mRNA 进行深度 RNA 测序与阿尔茨海默氏病相关的 tau蛋白病小鼠模型。我们多层次实验的结果通过对 RNA 的细胞类型特异性分辨率来定义慢性睡眠剥夺的全基因组影响处理以及识别慢性睡眠剥夺的细胞类型特异性翻译组特征，将提供了有关睡眠剥夺对 tau 蛋白发病机制的负面影响的重要见解阿尔茨海默氏病，可能导致开发新的疗法来对抗阿尔茨海默氏病睡眠不足对认知和神经退行性疾病的影响。