Molecular pathways connecting sleep, stress, metabolism and longevity

连接睡眠、压力、新陈代谢和长寿的分子途径

• 批准号: 10596563
• 负责人: Michael Warren Young
• 金额: $ 42.38万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596563
• 关键词: Affect; Binding; Biochemical; Biological Assay; Blood - brain barrier anatomy; Brain; Chronic; Chronic Insomnia; Clinical; Desire for food; Disease; Drosophila genus; Exposure to; Food; Genes; Genetic; Genetic Screening; Genetic study; Hereditary Disease; Human; Hunger; Ion Exchange; Longevity; Maps; Measurement; Mental Health; Metabolism; Molecular; Molecular Genetics; Monitor; Morphology; Motor Activity; Mutation; Nervous System Physiology; Neuroglia; Orthologous Gene; Pathway interactions; Permeability; Phase; Population; Proteins; Recovery; Role; Siblings; Sleep; Sleep Deprivation; Sleep Disorders; Social isolation; Stress; Time; Tissues; Wakefulness; biological adaptation to stress; biophysical properties; blood-brain barrier function; casein kinase I; circadian pacemaker; comparative; cryptochrome; economic impact; fly; gene product; human error; mutant; neuronal circuitry; novel; physical conditioning; response; restoration; sleep behavior; stressor; temporal measurement; tool; transcriptome sequencing

Project Summary/Abstract Genetic screens in Drosophila have identified mutations that significantly reduce both night- time and daytime sleep. Genes affected by these mutations are expressed in the blood-brain- barrier-forming subperineurial glia of the fly and alter the morphological and biophysical properties of the barrier. We have discovered novel genetic interactions among some of these mutations: surprisingly, certain mutant combinations restore both sleep and blood-brain-barrier function. We propose further studies that could reveal molecular pathways connecting their gene products and clarify their contributions to sleep and barrier function. We discovered that in wild type Drosophila the blood-brain barrier opens and closes with a rhythm that requires a circadian clock. We have also found that barrier permeability is closely connected to sleep need: sleep deprivation opens the barrier, but rebound sleep closes it. What is being exchanged across the barrier in such a dynamic fashion? Nervous system function is protected by a steep concentration gradient of K+ separating the haemolymph and brain. In our proposed studies we will develop tools to quantify K+ flux across the blood brain barrier with high temporal resolution in living flies. Are episodes of sleep and wakefulness correlated with these ion exchanges? Do such measurements reveal features of wake/sleep behavior that are not evident using standard locomotor activity monitoring? Our studies have also shown that sleep mutants reduce lifespan, but in a fashion that can be reversed by time-controlled access to food. These effects require a circadian clock and we will determine which tissues are responsible for this response and whether lifespan restoration depends on sleep recovery. Chronic exposure to psychogenic stressors can have profound, long-lasting effects on both physical and mental health and is often accompanied by a profound loss of sleep. Chronic social isolation provides a means by which a psychogenic stressor can be easily applied for an extended period, and we observe significant reductions in total sleep, day-time sleep, and night-time sleep in isolated flies when compared to sleep in siblings that are group reared. To search for genetic pathways that might respond to isolation-induced stress and depress sleep, comparative RNAseq assays were performed using Drosophila heads collected from group- reared flies, or from flies stressed through chronic isolation. Among the most highly responding genes are those thought to regulate appetite. These map to a small neuronal circuit which we will further characterize to determine its possible role in isolation-induced stress responses affecting sleep and hunger.

项目总结/摘要 果蝇的基因筛选已经发现了显著减少夜间和夜间活动的突变。 时间和白天的睡眠。受这些突变影响的基因在血脑中表达， 形成屏障的神经束膜下胶质的苍蝇，并改变形态和生物物理 屏障的特性。我们已经发现了一些新的遗传相互作用， 突变：令人惊讶的是，某些突变组合可以恢复睡眠和血脑屏障。 功能我们提出进一步的研究，可以揭示连接他们的分子途径。 基因产物，并阐明其对睡眠和屏障功能的贡献。我们发现 在野生型果蝇中，血脑屏障的打开和关闭有一种节奏， 生物钟我们还发现屏障通透性与睡眠密切相关 需要：睡眠剥夺打开了屏障，但反弹睡眠关闭了它。 以这样一种动态的方式跨越障碍进行交换？神经系统功能得到保护 通过K+的陡峭浓度梯度分离血淋巴和脑。在我们提出的 研究我们将开发工具来量化高时间内穿过血脑屏障的K+通量 解决活苍蝇。睡眠和清醒的发作是否与这些离子有关 交换？这样的测量是否揭示了唤醒/睡眠行为的特征，而这些特征不是 用标准的自发活动监测是很明显的我们的研究还表明睡眠 突变体减少寿命，但以一种可以通过时间控制访问来逆转的方式， 食物这些影响需要生物钟，我们将确定哪些组织是 负责这种反应，以及寿命的恢复是否取决于睡眠恢复。 长期暴露于心因性压力源会对两者产生深远而持久的影响 身体和精神健康，往往伴随着严重的睡眠不足。慢性 社会隔离提供了一种手段，通过这种手段，心理应激源可以很容易地应用于 我们观察到总睡眠、白天睡眠和 夜间睡眠在孤立的苍蝇相比，睡眠的兄弟姐妹，是集团饲养。到 寻找可能对隔离引起的压力和抑制睡眠做出反应的遗传途径， 比较RNAseq测定使用从组- 饲养的苍蝇，或通过长期隔离强调苍蝇。在回应最强烈的 基因被认为是调节食欲的基因。这些映射到一个小的神经元回路， 将进一步表征以确定其在隔离诱导的应激反应中的可能作用 影响睡眠和饥饿。