Genetic Analysis of Sleep Regulation

描述(申请人提供)：睡眠对人类健康的重要性已经得到了很好的描述，因为睡眠不足与神经行为、心血管和新陈代谢的后果有关。此外，人们越来越认识到睡眠障碍是常见的，事实上，据估计，每年因这些障碍而花费的资金高达数十亿美元。尽管如此，我们对睡眠的基本功能以及睡眠背后的分子和细胞途径的了解仍然很少，这限制了我们为睡眠障碍的治疗确定新的治疗靶点的能力。这项研究应用的总体目标是以果蝇黑腹果蝇为模型系统，了解睡眠调节的分子和遗传基础。利用果蝇作为遗传模型系统已经导致了许多基础性的发现，例如解锁了昼夜节律背后的分子机制。果蝇也被证明参与睡眠行为，果蝇和人类之间的许多信号通路是保守的。因此，果蝇非常适合于识别调节睡眠的新基因和分子。利用果蝇的基因筛查，我们已经鉴定出一个新的突变体，名为Wide Awag(WAKE)，它显示出睡眠显著减少，睡眠潜伏期显著增加(即，他们需要更长的时间才能入睡)。我们的初步研究表明，WAKE蛋白在促进觉醒的神经元回路中表达，并且WAKE的正常功能是增强GABA信号并抑制其表达的回路。在这一应用中，我们将通过实现以下目标来增加我们对睡眠调节的分子和细胞基础的理解：1)研究WAKE蛋白的调节和定位，2)识别WAKE功能所需的神经元回路，以及3)确定WAKE调节睡眠的机制。这些研究将加强我们对一种新的调节睡眠的分子的理解，因为大多数苍蝇和哺乳动物之间调节睡眠的信号通路是保守的，应该会对人类睡眠的分子机制有更深入的了解。

DESCRIPTION (provided by applicant): The importance of sleep in human health is well-described, as loss of sleep is associated with neurobehavioral, cardiovascular, and metabolic consequences. Furthermore, sleep disorders are increasingly recognized to be common, and indeed, it has been estimated that billions of dollars are spent each year as a result of these disorders. Despite this, our understanding of the basic function of sleep, as well as the molecular and cellular pathways underlying sleep, remain poorly understood, which limits our ability to identify new therapeutic targets for treatments of sleep disorders. The overall goal of this research application is to understand the molecular and genetic basis of sleep regulation, using the fruit fly Drosophila melanogaster as a model system. The use of Drosophila as a genetic model system has led to many fundamental discoveries, such as the unlocking of the molecular mechanisms underlying circadian rhythms. Fruit flies have also been demonstrated to engage in sleep behavior, and many of the signaling pathways between flies and humans are conserved. Thus, fruit flies are well-suited for the identification of novel genes and molecules that regulate sleep. Using a genetic screen in Drosophila, we have identified a novel mutant, named wide awake (wake), which exhibits a significant reduction in sleep, and a prominent increase in sleep latency (i.e., they take much longer to fall asleep). Our preliminary studies suggest that the WAKE protein is expressed in a neuronal circuit that promotes arousal and that the normal function of WAKE is to enhance GABA signaling and inhibit the circuit in which it is expressed. In this application, we will increase our understanding of the molecular and cellular basis of sleep regulation by carrying out the following aims: 1) investigate the regulation and localization of WAKE protein, 2) identify the neuronal circuits required for WAKE function, and 3) determine the mechanisms by which WAKE regulates sleep. These studies will enhance our understanding of a novel molecule that regulates sleep, and, because most signaling pathways regulating sleep between flies and mammals are conserved, should yield insights into the molecular mechanisms underlying sleep in humans.