Mechanism of sleep regulation by SIK3

SIK3对睡眠的调节机制

• 批准号: 10382293
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382293
• 关键词: Acute; Affect; Afferent Neurons; Animals; Auxins; Behavioral; Caenorhabditis elegans; Cell Nucleus; Cells; Cellular Stress; Charge; 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 Kinase; Proxy; RNA Interference; Regulation; Research; STK11 gene; Serine; Signal Transduction; Sleep; Sleep Deprivation; Sleep Disorders; Stress; System; Testing; Threonine; Transgenic Organisms; Work; cell injury; circadian; comorbidity; exoskeleton; experimental study; 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.

项目概要/摘要 睡眠和代谢紊乱共存的高患病率表明这些过程是整合的 在分子水平上，但这种整合的机制尚不清楚。最近发现 AMPK 结合我们的初步数据，家族成员 SIK3 是系统发育上保守的睡眠驱动调节因子 显示线虫 SIK 同源基因突变体动物的睡眠减少和能量储存增加 29，表明 SIK 是连接睡眠和能量稳态的关键节点。模型推动了这一点 提议认为 SIK 对特定神经元的能量水平有反应；低能量（即低 ATP 水平）导致 SIK 移动到细胞核中，通过 II 类 HDAC 的磷酸化 解除对促进睡眠和能量储备动员信号的基因的抑制。我们将测试这个模型 使用线虫秀丽隐杆线虫并做出以下假设： (1) 细胞能量电荷为 在睡眠驱动力增加的情况下较低。 (2)低能量条件下的KIN-29/SIK信号 调动能量储存并恢复细胞 ATP 水平和睡眠。 (3) KIN-29/SIK在以下方面发挥着敏锐的作用： 代谢反应性感觉神经元，调节睡眠诱导的 ALA 和 RIS 神经元；它的功能 在相同的神经元中调节脂肪储存。 (4) KIN-29/SIK促睡眠活性受核控制 import，受上游激酶 LKB1 和 PKA 调节。最后，（5）我们将进行探索性的 旨在通过进行试点基因筛查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 中的实验将通过以下方式阐明分子和细胞机制： SIK 的功能是调节动物睡眠和能量储存。目标 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 从线虫中获得的信息可以激发在哺乳动物中进行集中实验，并将加深我们的理解 患有睡眠调节障碍的患者。