Mechanism of sleep regulation by SIK3

项目摘要- 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C.突变动物的睡眠减少和能量储存增加。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SIG进入细胞核，在细胞核中，通过II类HDAC的磷酸化， 基因的信号，以促进睡眠和能量储备动员。我们将使用 线虫线虫 增加睡眠驱动力的条件。(2)KIN-29/SIK在低能量条件下发出信号以调动能量 储存和恢复细胞ATP水平和睡眠。(3)KIN-29/SIK在代谢反应性细胞中的急性功能 调节睡眠诱导ALA和RIS神经元的感觉神经元;它在相同的神经元中起作用， 调节脂肪储存。(4)KIN-29/SIK促进睡眠的活性受核输入控制，核输入受到调节， 上游激酶LKB 1和PKA。最后，（5）我们将通过进行试点来实现探索性目标 基因筛选，以发现kin-29突变体睡眠减少表型所需的新基因。 目的1-4中的实验将阐明SIKs发挥作用的分子和细胞机制， 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，将提供一个 连接到下一组关于困倦机制的假设。从《公约》获得的经验教训 线虫可以激励在哺乳动物中进行重点实验，并将告知我们对患者的理解。 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.