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.

项目摘要/摘要 果蝇中的遗传筛选已经确定了显着降低两个夜晚的突变 时间和白天睡觉。受这些突变影响的基因在血脑内表达 苍蝇的形成屏障亚磨性胶质神经胶质并改变形态和生物物理 屏障的性质。我们在其中一些发现了新的遗传相互作用 突变：令人惊讶的是，某些突变组合恢复了睡眠和血脑屏障 功能。我们提出了进一步的研究，可以揭示将其连接的分子途径 基因产品并阐明它们对睡眠和障碍功能的贡献。我们发现了这一点 在野生型果蝇中，血脑屏障打开并以一种需要的节奏闭合 昼夜节律。我们还发现，屏障渗透性与睡眠密切相关 需要：睡眠剥夺打开障碍，但反弹的睡眠使它关闭。有什么 以这种动态的方式在障碍物上交换？神经系统功能受到保护 通过陡峭的浓度梯度，将血液和大脑分开。在我们的建议中 研究我们将开发工具，以量化高颞的血脑屏障的K+通量 生命苍蝇的解决方案。是睡眠和清醒的情节与这些离子相关 交流？进行这样的测量揭示唤醒/睡眠行为的特征 使用标准的运动活动监测明显？我们的研究还表明睡眠 突变体降低寿命，但以时间控制的访问可以逆转的方式 食物。这些效果需要昼夜节律，我们将确定哪些组织是 负责此反应以及寿命恢复是否取决于睡眠恢复。 长期暴露于心理压力源会对这两者产生深远的持久影响 身心健康，通常会伴随着严重的睡眠丧失。慢性的 社会隔离提供了一种可以轻松应用心理压力源的手段 长时间的时间，我们观察到总睡眠，白天睡眠和 与在小组饲养的兄弟姐妹中睡觉相比，夜间睡眠孤立的苍蝇。到 寻找可能响应隔离引起的压力和降低睡眠的遗传途径， 使用从组中收集的果蝇头进行比较RNASEQ分析 饲养的苍蝇，或者是通过慢性隔离而压力的苍蝇。最有回应的 基因是被认为调节食欲的基因。这些地图是我们的小型神经元电路 将进一步表征以确定其在隔离引起的应力反应中的可能作用 影响睡眠和饥饿。