Mechanism of sleep regulation by SIK3

SIK3对睡眠的调节机制

• 批准号: 10601000
• 负责人: David Menassah Raizen
• 金额: $ 32.24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601000
• 关键词: Acute; Affect; Afferent Neurons; Animals; Auxins; Behavioral; Caenorhabditis elegans; Cell Nucleus; Cells; Cellular Stress; Charge; Communication; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Development; Diabetes Mellitus; Drowsiness; Exposure to; Face; Family member; Fatty acid glycerol esters; Future; Gene Expression; Genes; Genetic Screening; Glycogen; HDAC4 gene; High Prevalence; Histone Deacetylase; Homeostasis; Homologous Gene; Homologous Protein; Individual; Link; Mammals; Measures; Mediating; Metabolic; Metabolic Diseases; Modeling; Molecular; Movement; NADH; Nematoda; Neuroendocrine Cell; Neurons; Nuclear; Nuclear Import; Oxidative Phosphorylation; Oxygen Consumption; Patients; Phase; Phenotype; Phosphorylation; Phylogenetic Analysis; Process; Protein-Serine-Threonine Kinases; Proxy; Publishing; RNA Interference; Regulation; Research; STK11 gene; Signal Transduction; Sleep; Sleep Deprivation; Sleep Disorders; Stress; System; Testing; Transgenic Organisms; Work; cell injury; circadian; comorbidity; derepression; exoskeleton; experimental study; gene repression; histone deacetylase 2; knock-down; mutant; neural circuit; optogenetics; repaired; respiratory; sleep regulation; upstream kinase

PROJECT SUMMARY/ABSTRACT The high prevalence of coexistent sleep and metabolic disorders suggest that these processes are integrated at the molecular level, but mechanisms of this integration are unknown. The recent finding that the AMPK family member SIK3 is a phylogenetically conserved sleep drive regulator combined with our preliminary data showing both reduced sleep and elevated energy stores in animals mutant for the C. elegans SIK homolog kin- 29, suggests that SIKs are key nodes connecting sleep and energy homeostasis. The model motivating this proposal is that SIKs are responsive to the energy level in particular neurons; low energy (i.e. low ATP levels) result in the movement of SIK into the nucleus where, via phosphorylation of a class II HDAC it de-represses genes that signal to promote sleep and energy reserve mobilization. We will test this model using the nematode Caenorhabditis elegans and with the following hypotheses: (1) Cellular energy charge is lower under conditions of increased sleep drive. (2) KIN-29/SIK signals under conditions of low energy to mobilize energy stores and restore cellular ATP levels and sleep. (3) KIN-29/SIK functions acutely in metabolically-responsive sensory neurons that regulate the sleep-inducing ALA and RIS neurons; It functions in the same neurons to regulate fat stores. (4) KIN-29/SIK sleep-promoting activity is controlled by nuclear import, which is regulated by the upstream kinases LKB1 and PKA. Finally, (5) we will pursue an exploratory aim by performing a pilot genetic screen to discover new genes that are required for the reduced sleep phenotype of kin-29 mutants. Experiments in aims 1-4 will illuminate the molecular and cellular mechanism by which SIKs function to regulate animal sleep and energetic stores. Aim 5, in which we will identify new sleep genes, will provide a bridge into the next set of hypotheses regarding mechanisms of sleepiness. Lessons gained from the nematode can motivate focused experiments in mammals, and will inform our understanding of patients with disorders of sleep regulation.

项目摘要/摘要 共存睡眠和代谢障碍的高流行率表明这些过程已整合 在分子水平上，但是这种整合的机制尚不清楚。最近的发现AMPK 家庭成员SIK3是一种系统发育保守的睡眠驱动器调节器，并结合我们的初步数据 显示秀丽隐杆线虫sik同源物的动物突变体中的睡眠降低和能量储存升高 - 29，表明Siks是连接睡眠和能量稳态的关键节点。动机的模型 提议是锡克族对能量水平特别是神经元的反应。低能（即低ATP 级别）导致Sik进入核，其中通过II类HDAC IT的磷酸化 取消抑制基因，以促进睡眠和能量储备动员。我们将测试此模型 使用线虫秀丽隐杆线虫和以下假设：（1）细胞能量电荷为 在睡眠驱动器增加的条件下，较低。 （2）在低能条件下，Kin-29/Sik信号 动员能量存储并恢复细胞ATP水平并睡眠。 （3）kin-29/sik急性功能 代谢反应性的感觉神经元调节诱导睡眠的ALA和RIS神经元；它功能 在同一神经元中调节脂肪储存。 （4）KIN-29/SIK促进睡眠活动由核控制 导入，由上游激酶LKB1和PKA调节。最后，（5）我们将进行探索性 通过执行试点遗传屏幕来发现减少睡眠所需的新基因 KIN-29突变体的表型。目标1-4中的实验将通过 哪种锡克族可以调节动物睡眠和能量储存。 AIM 5，我们将确定新的睡眠 基因将为下一组有关嗜睡机制的假设提供桥梁。教训 从线虫中获得的可以激发哺乳动物的集中实验，并将告知我们的理解 患有睡眠调节疾病的患者。