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

描述（由申请人提供）：睡眠剥夺在美国人口中很常见，而且越来越普遍。睡眠不足有许多不良后果。这些问题包括行为改变、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，如胰岛素抵抗、食欲增加，是肥胖的一个危险因素。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，也就是说，个体之间的很大一部分差异是源于基因。阐明对睡眠缺失反应的遗传基础将使需要24/7活动的手术安排更加合理，并可能确定新的途径，这可能是未来改变睡眠缺失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很高的协议负担（在实验室中4天）。在此应用程序中，提出了一种基于小鼠研究的替代方法来识别负责基因。不同近交系小鼠对睡眠剥夺的反应不同，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造的多种基因不同的小鼠远交种。这一策略需要对大量小鼠进行研究

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.