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：
8527842
负责人：
Allan I Pack
金额：
$ 45.25万
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/8527842
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.

描述（由申请人提供）：剥夺睡眠是普遍的，并且在美国人群中的患病率增加。睡眠丧失会带来许多不利后果。其中包括行为改变，认知障碍，发生撞车的风险增加以及工作场所中的错误。此外，睡眠不足会导致胰岛素抵抗，食欲增加，是肥胖发展的危险因素。但是，由于睡眠损失产生的损害程度存在很大的个体差异。这是可遗传的，即，个体之间差异的很大一部分在oriin中是遗传的。阐明对睡眠损失反应的遗传基础将使需要24/7活动的操作中有更加理由的调度，并且可能会确定可能是未来药理方法的基础，以改变睡眠损失的后果。但是，进一步的研究以阐明人类涉及的基因是有挑战性的，因为检查对睡眠剥夺的反应需要昂贵的研究，并具有较高的协议负担（在实验室中为期四天）。在此应用中，根据小鼠的研究，提出了一种识别负责基因的替代方法。小鼠对睡眠剥夺的反应在近交菌株之间有所不同，但导致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小鼠菌株，这些小鼠在遗传上都不同。该策略需要研究大量小鼠（在此应用程序中，800）以高通量方式。因此，基于数字视频分析的新型高通量策略将评估对睡眠剥夺的反应。视频分析不仅提供了对睡眠和唤醒的准确估计，还提供了睡眠 - 比左眼运动（REM）睡眠和非比重眼运动（NREM）睡眠的阶段。所有小鼠不仅将被表型，而且将基于具有7,000个单核苷酸多态性的新基因分型芯片进行基因分型。这种方法允许鉴定与该定量性状相关的小鼠基因组的一小部分。此外，小鼠可以维持的正常清醒持续时间也将同时评估。这也是一个可遗传的特征与睡眠困难的常见问题高度相关。在两个定量特征中，将对来自协作跨线的相关小鼠进行验证研究。未来的研究还将使用经过睡眠损失且已有DNA的良好表征个体的样本扩展了对人类种群的研究。