Genetic Approaches to Sleep/Wake and Response to Sleep Loss in Mice

小鼠睡眠/觉醒的遗传方法以及对睡眠不足的反应

基本信息

批准号：
8372470
负责人：
Allan I Pack
金额：
$ 43.63万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8372470
关键词：
Address American Behavioral Bioinformatics Biological Models Chronic Cognition Complex DNA Data Desire for food Development Disease Electrodes Excessive Daytime Sleepiness Future Genes Genetic Genetic Variation Genome Genotype Human Impairment Inbred Strain Individual Individual Differences Insulin Resistance Investigation Laboratories Lead Metabolic Mouse Strains Mus Narcolepsy Obesity Obstructive Sleep Apnea Operative Surgical Procedures Pathway interactions Patients Phenotype Population Prevalence Protocols documentation Quantitative Trait Loci REM Sleep Research Resources Restless Legs Syndrome Risk Risk Factors Role Sampling Schedule Single Nucleotide Polymorphism Sleep Sleep Apnea Syndromes Sleep Deprivation Sleep Disorders Sleep Stages Sleeplessness Source Twin Studies Variant Vehicle crash Wakefulness Work Workplace adverse outcome base behavioral impairment digital genetic resource implantation increased appetite mouse genome non rapid eye movement novel operation pressure rapid eye movement response sleep regulation tool trait validation studies

项目摘要

DESCRIPTION (provided by applicant): Sleep deprivation is common and increasing in prevalence in the American population. Loss of sleep has a number of adverse consequences. These include behavioral changes, impairment of cognition with an increased risk of motor vehicle crashes, and errors in the workplace. Moreover, sleep loss leads to metabolic changes with insulin resistance, increased appetite and is a risk factor for development of obesity. There are, however, substantial individual differences in the degree of impairment produced by sleep loss. This is heritable, i.e., a large part of the difference between individuals is genetic in oriin. Elucidating the genetic basis of the response to sleep loss will enable a more rationale scheduling in operations that require 24/7 activity, and will likely identify novel pathways that could be the basis of future pharmacological approaches to alter the consequences of sleep loss. Further study to elucidate genes involved in humans is, however, challenging since examination of the response to sleep deprivation requires expensive studies with a high protocol burden (four days in a laboratory). In this application an alternative approach to identify responsible genes is proposed, based on studies in mice. Response to sleep deprivation in mice varies between inbred strains but the gene variants responsible for this difference are unknown. This proposal plans to take advantage of the recently created diverse outbred strain of mice which are all genetically different. This strategy requires study of a large number of mice (in this application, 800) in a high throughput fashion. Hence, response to sleep deprivation will be assessed by a novel high throughput strategy based on digital video analysis. Video analysis not only provides accurate estimates of sleep and wake, but also of the stages of sleep-rapid-eye movement (REM) sleep and non-rapid-eye movement (NREM) sleep. All mice will not only be phenotyped but will be genotyped based on a new genotyping chip with 7,000 single nucleotide polymorphisms. This approach allows identification of a small region of the mouse genome associated with this quantitative trait. In addition, the normal duration of wakefulness that a mouse can sustain will also be simultaneously assessed. This, too, is a heritable trait that is highly relevant to the common problem of sleeping difficulty. Validation studies in relevant mice from the collaborative cross lines will be employed for both quantitative traits. Future studies will also extend this investigation into human populations using samples of well characterized individuals who have been studied with sleep loss and whose DNA is already available. PUBLIC HEALTH RELEVANCE: Sleep deprivation is common in the American population. It has adverse consequences in the form of errors in the workplace and increased risk of crashes. There are also consequences in terms of altered appetite control and sleep loss is a risk factor for obesity. But these consequences vary markedly between individuals and this difference is genetic. This proposal is to address the gene variants responsible for this difference using the recently created Diversity Outbred panel of mice that are all genetically different. Future studies to elucidate the role of these variants in human populations are also described.

描述（由申请人提供）：睡眠不足在美国人口中很常见，而且越来越普遍。睡眠不足会带来许多不良后果。这些包括行为改变、认知障碍（机动车碰撞风险增加）以及工作场所的错误。此外，睡眠不足会导致代谢变化，导致胰岛素抵抗、食欲增加，并且是肥胖的危险因素。然而，睡眠不足造成的损害程度存在很大的个体差异。这是可遗传的，即个体之间的差异很大一部分是起源于遗传的。阐明对睡眠不足反应的遗传基础将使需要 24/7 活动的操作更加合理地安排，并且可能会确定新的途径，这些途径可能成为未来改变睡眠不足后果的药理学方法的基础。然而，进一步研究阐明与人类有关的基因具有挑战性，因为检查对睡眠剥夺的反应需要昂贵的研究和高协议负担（在实验室进行四天）。在本申请中，基于小鼠研究，提出了一种识别相关基因的替代方法。不同近交系小鼠对睡眠剥夺的反应有所不同，但造成这种差异的基因变异尚不清楚。该提案计划利用最近创建的多种近交系小鼠，这些小鼠的基因都不同。该策略需要对大量小鼠进行研究（在此应用中为 800）以高吞吐量方式。因此，对睡眠剥夺的反应将通过基于数字视频分析的新型高通量策略进行评估。视频分析不仅可以准确估计睡眠和觉醒，还可以准确估计睡眠阶段——快速眼动 (REM) 睡眠和非快速眼动 (NREM) 睡眠。所有小鼠不仅会进行表型分析，还会基于具有 7,000 个单核苷酸多态性的新型基因分型芯片进行基因分型。这种方法可以识别与这种数量性状相关的小鼠基因组的一小部分区域。此外，还将同时评估小鼠可以维持的正常清醒持续时间。这也是一种可遗传的特征与睡眠困难这一常见问题高度相关。对来自协作交叉系的相关小鼠进行验证研究将用于这两个数量性状。未来的研究还将把这项研究扩展到人类群体，使用经过研究的睡眠不足且 DNA 已经获得的特征明确的个体样本。公共卫生相关性：睡眠不足在美国人中很常见。它会产生不利后果，导致工作场所出现错误并增加撞车风险。食欲控制改变也会产生后果，睡眠不足是肥胖的一个危险因素。但这些后果因人而异，而且这种差异是遗传性的。该提案旨在利用最近创建的 Diversity Outbred 小鼠小组来解决导致这种差异的基因变异，这些小鼠的基因都不同。未来的研究还描述了阐明这些变异在人群中的作用的方法。