Molecular and Neural Mechanisms of Sleep Regulation by TARANIS

TARANIS 睡眠调节的分子和神经机制

基本信息

批准号：
9385776
负责人：
Kyunghee Koh
金额：
$ 3.5万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9385776
关键词：
Activins Address Adult Affect Anatomy Arousal Binding Biochemical Biological Process CDC2 Protein Kinase Cell Cycle Progression Cell Cycle Proteins Cells Cyclin A Cyclin-Dependent Kinases Data Development Drosophila genus Exhibits Genes Genetic Genetic Screening Genetic Transcription Growth Health Homeostasis Human Hypothalamic structure Interneurons Lead Mediator of activation protein Mitotic Modeling Molecular Mutation Neurologic Neurons Pathway interactions Patients Phosphotransferases Polysomnography Population Process Productivity Property Proteins Quality of life Recording of previous events Regulation Regulatory Pathway Reporter Role Safety Signal Transduction Signaling Molecule Site Sleep Sleep Deprivation Sleep Disorders Sleep disturbances Synapses Techniques Testing Time Transcript Transcriptional Regulation Workplace arm base cdc Genes circadian pacemaker cognitive function experimental study fly imaging study in vivo insight knock-down mutant neural circuit neuromechanism new therapeutic target novel overexpression protein expression public health relevance reconstruction sleep regulation

项目摘要

DESCRIPTION (provided by applicant): Sleep serves essential biological functions, and is conserved from flies to humans. Sleep disturbance is a common health problem that impinges on quality of life, workplace productivity, and public safety. Sleep usually occurs at specific tims of day and lasts for certain amounts of time. These two features of sleep are controlled by distinct molecular mechanisms. Whereas the molecular and anatomical basis of the circadian clock, which controls when we sleep, has been investigated extensively, the molecules and neural circuits underlying sleep homeostasis that regulates sleep duration are not well understood. Identification of novel genes and circuits that control sleep duration would facilitate elucidation of this mysterious biological process. The Drosophila model for sleep is well suited for discovery of new sleep-modulating genes through unbiased genetic screens. Using a forward-genetic screen for short-sleeping mutants, we isolated a novel sleep gene, taranis (tara). Mutations in tara result in a marked (up to 80%) reduction of sleep duration. [[Importantly tara mutants exhibit decreased levels of REDEYE (RYE), whose expression is regulated by homeostatic sleep drive. Thus isolation of TARA provides an exciting opportunity to investigate the molecular mechanisms underlying sleep homeostasis, a critical process that is poorly understood. Previous findings suggest that TARA and its mammalian homologs are involved in transcriptional regulation and cell cycle progression, and contain a Cyclin A (CycA)-binding homology domain. Notably, CycA, another cell cycle protein, was recently shown to be a sleep-promoting factor, but the molecular function of CycA in sleep is not well understood. Our preliminary studies suggest that TARA promotes sleep by two complementary pathways: 1) by upregulating protein expression of CycA and inhibiting Cdk1 (a Cyclin-dependent kinase that binds CycA and negative regulator of sleep), and 2) by upregulating transcription of dawdle (daw), an Activin-like signaling molecule and positive regulator of sleep. Further, our data identify ~14 CycA expressing cells in the pars lateralis (PL), which is analogous to the mammalian hypothalamus, as a novel sleep center. Building on these preliminary data, we propose to (Aim 1) determine how TARA interacts with other cell cycle proteins to regulate sleep, (Aim 2) how TARA interacts with daw to regulate sleep, and whether DAW acts as a sleep-inducing homeostatic signal, and (Aim 3) determine where and when TARA is required for sleep, and how the PL neurons connect to other sleep centers. The proposed experiments will yield significant mechanistic insights into sleep homeostasis.]]

描述（由申请人提供）：睡眠具有重要的生物学功能，从苍蝇到人类都有。睡眠障碍是影响生活质量、工作场所生产力和公共安全的常见健康问题。睡眠的这两个特征是由不同的分子机制控制的，在控制我们睡眠的生物钟的分子和解剖学基础中，睡眠的分子和神经回路得到了特别的研究。调节睡眠持续时间的体内平衡尚不清楚，识别控制睡眠持续时间的新基因和电路将有助于。果蝇睡眠模型非常适合通过无偏见的遗传筛选发现新的睡眠调节基因，我们利用针对短睡眠突变体的前向遗传筛选，分离出了一种新的睡眠基因——taranis（tara）。 tara 突变导致睡眠持续时间显着缩短（高达 80%）[[重要的是，tara 突变体的 REDEYE (RYE) 表达水平降低。因此，TARA 的分离为研究睡眠稳态的分子机制提供了一个令人兴奋的机会，而此前的研究结果表明，TARA 及其哺乳动物同源物参与了转录调节和细胞周期进程。，并含有细胞周期蛋白 A (CycA) 结合同源结构域值得注意的是，另一种细胞周期蛋白 CycA 最近被证明是一种睡眠促进因子，但 CycA 的分子功能在我们的初步研究表明，TARA 通过两种互补途径促进睡眠：1) 通过上调 CycA 的蛋白表达并抑制 Cdk1（一种结合 CycA 和睡眠负调节因子的细胞周期蛋白依赖性激酶），2) 通过上调 Dawdle（daw）的转录，dawdle 是一种激活素样信号分子和睡眠的正调节因子。此外，我们的数据在外侧部发现了约 14 个表达 CycA 的细胞。（PL），类似于哺乳动物下丘脑，作为一个新的睡眠中心，基于这些初步数据，我们建议（目标 1）确定 TARA 如何与其他细胞周期蛋白相互作用来调节睡眠，（目标 2）TARA 如何相互作用。与 Daw 相互作用来调节睡眠，以及 DAW 是否充当睡眠诱导稳态信号，以及（目标 3）确定何时何地需要 TARA 进行睡眠，以及 PL 神经元如何连接到其他睡眠所提出的实验将对睡眠稳态产生重要的机制见解。]]