Identification of Sleep Substances in the Brain Using Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry

使用基质辅助激光解吸电离飞行时间质谱法鉴定大脑中的睡眠物质

• 批准号: 10647134
• 负责人: ORIE T SHAFER
• 金额: $ 23.55万
• 依托单位: ADVANCED SCIENCE RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647134
• 关键词: Address; Animals; Automobile Driving; Biological; Brain; Cardiovascular Diseases; Charge; Coupled; Drosophila genus; Drowsiness; Epidemic; Exertion; Future; Health; Human; Inflammatory; Investigation; Liquid Chromatography; MALDI-TOF Mass Spectrometry; Mechanics; Mediating; Mediator; Mental Health; Metabolic; Methods; Modeling; Molecular; Nature; Nervous System; Performance; Physiological; Process; Productivity; Recovery; Safety; Signal Transduction; Sleep; Sleep Deprivation; Sleep Disorders; Sleep disturbances; Sleeplessness; Slow-Wave Sleep; Societies; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stress; System; Time; Wakefulness; Well in self; Work; World Health Organization; awake; candidate identification; circadian pacemaker; experimental study; falls; fly; improved; improvement on sleep; insight; model organism; nervous system disorder; neural; neuromechanism; neuroregulation; physical conditioning; pressure; prevent; response; sleep regulation; social; tandem mass spectrometry

Abstract Sleep is a basic biological need and sufficient sleep is required for physical and mental health. Reduced or disordered sleep contributes to an array of metabolic, inflammatory, cardiovascular, and neurological disorders, reduces productivity and performance, and is a threat to public safety. Understanding the control of sleep is therefore critical for human health and society. Sleep pressure (or sleepiness) has long been thought to be driven by substances that accumulate in the brain, where they promote sleep by acting on neural centers of sleep control. The identification of molecular mediators of sleep pressure in the brain would be highly significant, in that it would provide obvious targets for the improvement of daily sleep. Here we propose a large and unbiased screen for molecules that the fit the criteria for sleep promoting substances that drive daily changes in sleep pressure and promote homeostatic increases in sleep following sleep deprivation. To this end we have developed methods to differentiate molecules that rise with increasing sleep pressure from those that rise in direct response to the mechanical perturbation necessary to keep animal subjects awake. In doing so we have addressed a fundamental challenge to the identification of molecular correlates of sleep pressure. Using Matrix Assisted Laser Desorption/Ionization – Time of Flight Mass Spectrometry, we will identify molecules whose abundance tracks sleep pressure within the central brain, where sleep is controlled. The identification of candidate sleep substances will set the stage for new mechanistic investigations of sleep in Drosophila whose aim is to identify conserved molecular mechanisms of its homeostatic control. Given the existence of sleep-like states across the animal kingdom and the presence of homeostatic sleep control even in animals with extremely simple nervous systems, discoveries made in Drosophila are likely to reveal conserved features physiological systems regulating sleep.

抽象的 睡眠是基本的生物需求，充足的睡眠是身心健康所必需的。 睡眠障碍会导致一系列代谢、炎症、心血管和神经系统疾病 失调，降低生产力和绩效，并对公共安全构成威胁。 因此，睡眠对于人类健康和社会至关重要。 据认为是由大脑中积累的物质驱动的，它们通过作用于大脑来促进睡眠 睡眠控制的神经中枢的识别将有助于识别大脑中睡眠压力的分子介质。 非常重要，因为它将为改善日常睡眠提供明显的目标。 提出对符合睡眠促进物质标准的分子进行大规模且公正的筛选 驱动睡眠压力的日常变化并促进睡眠后睡眠的稳态增加 为此，我们开发了区分随增加而上升的分子的方法。 睡眠压力来自那些直接响应于保持睡眠所必需的机械扰动而上升的睡眠压力 通过这样做，我们解决了识别的根本挑战。 使用基质辅助激光解吸/电离 - 飞行时间的分子相关性。 通过质谱分析，我们将识别其丰度跟踪中枢睡眠压力的分子 大脑是控制睡眠的地方，候选睡眠物质的识别将为新的睡眠物质奠定基础。 对果蝇睡眠的机制研究，其目的是确定保守的分子机制 鉴于整个动物界和人类都存在类似睡眠的状态。 即使在神经系统极其简单的动物中也存在稳态睡眠控制，发现 果蝇制造的基因可能会揭示调节睡眠的生理系统的保守特征。