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.

项目概要/摘要 果蝇的基因筛查发现了一些突变，可以显着减少夜间 时间和白天睡眠。受这些突变影响的基因在血脑中表达 果蝇的屏障形成神经束膜下神经胶质细胞并改变形态和生物物理 屏障的属性。我们发现了其中一些之间新的遗传相互作用 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。我们建议进一步的研究可以揭示连接它们的分子途径 基因产物并阐明它们对睡眠和屏障功能的贡献。我们发现 在野生型果蝇中，血脑屏障以一定的节奏打开和关闭，需要 生物钟。我们还发现屏障通透性与睡眠密切相关 需要：睡眠不足会打开障碍，但反弹睡眠会关闭它。什么是存在 以如此动态的方式跨越障碍进行交换？神经系统功能受到保护 通过 K+ 的陡峭浓度梯度将血淋巴和大脑分开。在我们提出的 研究中我们将开发工具来量化 K+ 穿过血脑屏障的通量 活蝇的分辨率。睡眠和觉醒的发作与这些离子相关吗 交流？这些测量是否揭示了唤醒/睡眠行为的特征，而不是 使用标准运动活动监测是否明显？我们的研究还表明，睡眠 突变体会缩短寿命，但这种方式可以通过时间控制的访问来逆转 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恢复是否取决于睡眠恢复。 长期暴露于心因性压力源会对双方产生深远、持久的影响 身体和心理健康状况不佳，并且常常伴有严重的睡眠不足。慢性的 社会隔离提供了一种可以轻松应对心因性压力源的方法 在较长一段时间内，我们观察到总睡眠时间、白天睡眠时间和睡眠时间显着减少 与群体饲养的兄弟姐妹的睡眠相比，孤立的果蝇的夜间睡眠。到 寻找可能应对隔离引起的压力和抑制睡眠的遗传途径， 使用从组中收集的果蝇头进行比较 RNAseq 测定 饲养的苍蝇，或通过长期隔离而受到压力的苍蝇。其中反应最热烈的 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电路，我们 将进一步表征以确定其在隔离引起的应激反应中可能发挥的作用 影响睡眠和饥饿。