Mechanism of sleep regulation by SIK3

SIK3对睡眠的调节机制

• 批准号: 10570655
• 负责人: David Menassah Raizen
• 金额: $ 5.69万
• 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/10570655
• 关键词: Acute; Adipocytes; Adipose tissue; Affect; Afferent Neurons; African-American Graduate Student; Animal Model; Animals; Behavior Control; Biochemical; Biomedical Research; CRISPR/Cas technology; Caenorhabditis elegans; Cell Nucleus; Cells; Charge; Chloride Channels; Complement; Couples; Cyclic AMP-Dependent Protein Kinases; Data; Diabetes Mellitus; Disease; Drowsiness; Endocrine; Family member; Fatty acid glycerol esters; Future; Genes; Genetic Screening; Goals; Grant; High Prevalence; Histamine; Histone Deacetylase; Homeostasis; Homologous Gene; Imaging Device; Individual; Knowledge; Link; Mammals; Measures; Mediating; Mentors; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Modeling; Molecular; Movement; Nematoda; Neuraxis; Neuroendocrine Cell; Neurons; Neurosciences; Nuclear Import; Oxidants; Paraquat; Parents; Patients; Peripheral; Pharmacogenetics; Phenotype; Phosphorylation; Phosphotransferases; Phylogenetic Analysis; Process; Publishing; ROS1 gene; Reactive Oxygen Species; Regulation; Reporting; Research; Research Activity; Research Personnel; Research Project Grants; Resistance; Role; STK11 gene; Science; Signal Transduction; Site; Sleep; Sleep Disorders; Sleeplessness; Superoxide Dismutase; Talents; Technical Expertise; Techniques; Testing; Tissues; Training; Transgenic Organisms; Triglycerides; Underrepresented Students; Work; antioxidant enzyme; base; calcium indicator; career development; catalase; computerized tools; conditional knockout; experimental study; fatty acid oxidation; genetic approach; innovation; mutant; overexpression; parent grant; pre-doctoral; relating to nervous system; salt-inducible kinase; sleep behavior; sleep regulation; tool; tool development; upstream kinase

Project Summary – PARENT APPLICATION 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 - 父申请 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是一种系统发育连接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。低能量（即低ATP水平） 导致Sik进入核的运动，在该细胞核中，通过II类HDAC的光谱化，它会取消抑制 信号以促进睡眠和能量储备动员的基因。我们将使用 线虫秀丽隐杆线虫和以下假设：（1）在 睡眠驱动力增加的条件。 （2）低能条件下的KIN-29/SIK信号动员能量 存储并恢复细胞ATP水平和睡眠。 （3）Kin-29/Sik在代谢响应中急性功能 调节诱导睡眠的ALA和RIS神经元的感觉神经元；它在同一神经元中起作用 调节脂肪存储。 （4）KIN-29/SIK促进睡眠活动受核进口的控制，该活动受调节 通过上游激酶LKB1和PKA。最后，（5）我们将通过执行飞行员来追求探索目标 遗传筛选以发现kin-29突变体睡眠表型减少所需的新基因。 AIM 1-4中的实验将阐明siks功能的分子和细胞机制 调节动物睡眠和充满活力的商店。 AIM 5，我们将确定新的睡眠基因，将提供一个 关于嗜睡机制的下一组假设。从 线虫可以激发哺乳动物的集中实验，并将告知我们对患者的理解 睡眠调节疾病。