Genetic Analysis of Sleep Regulation

睡眠调节的基因分析

• 批准号: 9094706
• 负责人: Mark N Wu
• 金额: $ 33.72万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9094706
• 关键词: Address; Antibodies; Arousal; Behavior; Behavioral; Biological Assay; Biological Models; Brain; Cardiovascular system; Cell membrane; Cells; Circadian Rhythms; Co-Immunoprecipitations; Complex; Cultured Cells; Data; Disease; Dominant Genetic Conditions; Drosophila genus; Drosophila melanogaster; Exhibits; Genes; Genetic Models; Genetic Screening; Genomics; Goals; Head; Health; Human; Imagery; Kinetics; Lead; Mammals; Measures; Metabolic; Modeling; Molecular; Molecular Genetics; Names; Neurons; Pathway interactions; Pattern; Phenotype; Pigments; Proteins; Recovery; Regulation; Reporter; Research; Signal Pathway; Signal Transduction; Sleep; Sleep Deprivation; Sleep Disorders; Study models; Time; Transgenic Organisms; Western Blotting; Xenopus oocyte; awake; base; falls; fly; forward genetics; gamma-Aminobutyric Acid; gene cloning; genetic analysis; insight; knock-down; meetings; mutant; neural circuit; neurobehavioral; neuronal circuitry; new therapeutic target; novel; sleep regulation; trafficking

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.

描述（由申请人提供）：睡眠在人类健康中的重要性已得到充分描述，因为睡眠不足与神经行为、心血管和代谢后果相关。此外，睡眠障碍越来越被认为是常见的，事实上，据估计，由于这些障碍，每年花费数十亿美元。尽管如此，我们对睡眠的基本功能以及睡眠的分子和细胞途径的理解仍然很不清楚，这限制了我们识别治疗睡眠障碍的新治疗靶点的能力。这项研究应用的总体目标是了解睡眠调节的分子和遗传基础，使用果蝇作为模型系统。使用果蝇作为遗传模型系统已经导致了许多基本的发现，例如解开昼夜节律的分子机制。果蝇也被证明参与睡眠行为，并且果蝇和人类之间的许多信号通路是保守的。因此，果蝇非常适合鉴定调节睡眠的新基因和分子。使用果蝇中的遗传筛选，我们已经鉴定出一种新的突变体，称为宽醒（wake），其表现出睡眠显著减少和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蛋白在促进唤醒的神经元回路中表达，WAKE的正常功能是增强GABA信号传导并抑制其表达的回路。在本申请中，我们将通过执行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。这些研究将增强我们对一种调节睡眠的新分子的理解，而且，由于调节苍蝇和哺乳动物之间睡眠的大多数信号通路是保守的，因此应该能够深入了解人类睡眠的分子机制。