Mechanism of sleep regulation by SIK3

项目总结/摘要 睡眠和代谢紊乱并存的高患病率表明，这些过程是一体化的 在分子水平上，但这种整合的机制是未知的。最近发现AMPK 家族成员SIK 3是一个遗传上保守的睡眠驱动调节因子，结合我们的初步数据， 显示了C. elegans SIK homolog kin- 29，表明SIKs是连接睡眠和能量稳态的关键节点。激发这一点的模型 一种建议是，SIKs对特定神经元的能量水平有反应;低能量（即低ATP 水平）导致了SIG进入细胞核，在那里，通过II类HDAC的磷酸化， 去抑制基因的信号，以促进睡眠和能量储备动员。我们将测试这个模型 使用线虫秀丽隐杆线虫，并具有以下假设：（1）细胞能荷是 在睡眠驱动力增加的情况下降低。(2)KIN-29/SIK信号在低能量条件下， 调动能量储存，恢复细胞ATP水平和睡眠。(3)KIN-29/SIK在以下情况中发挥急性作用： 调节睡眠诱导ALA和RIS神经元的代谢反应性感觉神经元;其功能 来调节脂肪储存。(4)KIN-29/SIK的促睡眠活性受核因子的调控 输入，受上游激酶LKB 1和PKA调节。（5）我们将探索 目的是进行一项试点基因筛查，以发现睡眠减少所需的新基因， kin-29突变体的表型。目标1-4中的实验将阐明分子和细胞机制， SIKs的功能是调节动物的睡眠和能量储存。目标5，我们将识别新的睡眠 基因，将提供一个桥梁，进入下一套假设有关的机制，嗜睡。教训 从线虫中获得的信息可以激励在哺乳动物中进行重点实验，并将为我们的理解提供信息。 睡眠调节紊乱的患者。

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.