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

描述（由申请人提供）：睡眠不足在美国人口中很常见，并且患病率正在增加。睡眠不足会产生许多不良后果。这些包括行为变化，认知障碍与机动车碰撞的风险增加，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，睡眠不足所造成的损害程度存在很大的个体差异。这是遗传的，即，个体之间的差异很大一部分是起源基因。阐明对睡眠丧失的反应的遗传基础将使需要24/7活动的操作更加合理，并可能确定新的途径，这些途径可能是未来改变睡眠丧失后果的药理学方法的基础。然而，进一步研究以阐明涉及人类的基因是具有挑战性的，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（在实验室中四天）。在本申请中，基于小鼠中的研究，提出了鉴定负责基因的替代方法。小鼠对睡眠剥夺的反应因近交系而异，但造成这种差异的基因变异尚不清楚。这项提案计划利用最近创造的各种远系杂交小鼠品系，这些品系的基因都不同。这一策略需要对大量小鼠进行研究 (in本申请800）。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。视频分析不仅提供了对睡眠和觉醒的准确估计，而且还提供了对睡眠-快速眼动（REM）睡眠和非快速眼动（NREM）睡眠阶段的准确估计。所有小鼠不仅将进行表型分析，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。这种方法允许识别与该数量性状相关的小鼠基因组的小区域。此外，还将同时评估小鼠可维持的正常清醒持续时间。这也是一种遗传特征， 与常见的睡眠问题密切相关。将对来自协作杂交系的相关小鼠进行两种数量性状的验证研究。未来的研究还将使用已被研究过睡眠不足且其DNA已经可用的良好表征的个体样本将这项调查扩展到人类群体。

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.