Mechanism of sleep regulation by SIK3

项目摘要/摘要 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 SIKs对能量水平做出反应，特别是神经元；低能量(即低ATP 水平)导致SIK进入细胞核，在那里，通过II类HDAC它的磷酸化 抑制促进睡眠和能量储备动员的信号基因。我们将测试这一型号 以线虫秀丽线虫为研究对象，假设：(1)细胞能荷为 在睡眠驱动力增强的情况下较低。(2)低能量条件下的KIN-29/SIK信号 调动能量储备，恢复细胞内的ATP水平和睡眠。(3)KIN-29/SIK在 调节睡眠诱导的ALA和RIS神经元的代谢反应感觉神经元；它的功能 在相同的神经元中调节脂肪储存。(4)KIN-29/SIK促眠活性受核调控 导入，受上游蛋白激酶LKB1和PKA的调控。最后，(5)我们将进行探索性的 目的是通过进行试点基因筛查来发现睡眠减少所需的新基因 KIN-29突变体的表型。AIMS 1-4的实验将通过以下方式阐明分子和细胞机制 它具有调节动物睡眠和能量储存的功能。目标5，我们将在其中识别新的睡眠 基因，将为下一套关于嗜睡机制的假说提供桥梁。教训 从线虫中获得的信息可以激发在哺乳动物身上进行有针对性的实验，并将有助于我们理解 有睡眠调节障碍的患者。

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.