Mechanism of sleep regulation by SIK3

项目摘要-父应用程序 睡眠和代谢紊乱并存的高发病率表明，这些过程是完整的。 在分子水平上，但这种整合的机制尚不清楚。最近的研究发现，AMPK 结合我们的初步数据，家族成员SIK3是一种系统发育保守的睡眠驱动调节因子 在秀丽线虫同源亲属突变的动物中，表现出睡眠减少和能量储存增加- 29，表明SIKS是连接睡眠和能量平衡的关键节点。推动这一点的模式 建议认为SIKS对能量水平，特别是神经元的能量水平有反应；低能量(即低ATP水平) 导致SIK进入细胞核，在那里，通过II类HDAC的磷酸化，它抑制 促进睡眠和能量储备动员的基因。我们将使用 线虫和秀丽线虫在以下假设下：(1)细胞能量电荷在 睡眠驱动力增强的条件。(2)KIN-29/SIK信号在低能量条件下动员能量 存储和恢复细胞内的ATP水平和睡眠。(3)KIN-29/SIK在代谢反应中发挥重要作用 调节睡眠诱导的ALA和RIS神经元的感觉神经元；它在相同的神经元中发挥作用 监管脂肪储存。(4)KIN-29/SIK促眠活性受核进口调控 由上游的LKB1和PKA激活。最后，(5)我们将通过进行试点来追求探索性目标 基因筛查，以发现KIN-29突变体睡眠减少表型所需的新基因。 AIMS 1-4中的实验将阐明siks发挥作用的分子和细胞机制。 规范动物睡眠和能量储备。在目标5中，我们将识别新的睡眠基因，将提供 进入下一组关于嗜睡机制的假说。从改革中吸取的经验教训 线虫可以在哺乳动物身上激发有针对性的实验，并将有助于我们对患有 睡眠调节障碍。

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.