The role of neural translin in metabolic control of sleep

建议书摘要 睡眠、食欲和能量动态平衡的神经调节对动物的生存至关重要，在严格的 进化压力。睡眠失调与肥胖、糖尿病和代谢性疾病密切相关。 尽管与新陈代谢和睡眠相关的疾病普遍存在，但神经和遗传过程 目前尚不清楚这两个系统之间的相互作用。这项提案将研究基因和 神经元调节睡眠以应对新陈代谢的变化。苍蝇和哺乳动物一样，能有效地调节睡眠。 根据他们的营养需求。具体地说，苍蝇和哺乳动物会抑制睡眠以应对 饥饿，大概是为了引发觅食行为。果蝇中强大的遗传学允许精确地 描述调节行为和代谢过程的基因。我最近进行了一项针对神经元的 对1100多个基因的RNA干扰筛选揭示了代谢所需的许多靶点 对睡眠的调节。特别是，这一筛选分离了翻译蛋白(Trsn)，这是一种高度结合mRNA/DNA的蛋白 从苍蝇到人类的保护。神经元特异性基因敲除或trsn基因突变导致果蝇失败 饥饿时抑制睡眠，但有正常的能量储存，trsn在整个门类中高度保守，并具有 在哺乳动物代谢功能中的假定作用。这项提议试图描述细胞和 确定睡眠和代谢状态如何整合的trsn的神经解剖学功能。这项工作将 确定新陈代谢和睡眠调节之间的关键联系，为研究提供新的途径 对人类健康有潜在影响的睡眠喂养相互作用。基因调控的功能研究 睡眠-新陈代谢的相互作用将为理解行为的代谢调节提供基础 并进一步加深我们对肥胖、睡眠障碍和糖尿病的理解。

Proposal Summary Neural regulation of sleep, appetite and energy homeostasis is critical to an animal's survival and under stringent evolutionary pressure. Dysregulation of sleep is strongly linked to obesity, diabetes, and metabolic disease. Despite the prevalence of disorders associated with metabolism and sleep, the neural and genetic processes that regulate interactions between these two systems is unclear. This proposal will investigate how genes and neurons modulate sleep in response to changes in metabolism. Flies, like mammals, potently modulate sleep in accordance with their nutritional needs. Specifically, flies and mammals suppress sleep in response to starvation, presumably to initiate food-seeking behavior. Powerful genetics in the fruit fly allow for precise characterization of genes regulating behavioral and metabolic processes. I recently carried out a neuron-specific RNA interference screen of over 1100 genes revealed numerous targets that are required for metabolic regulation of sleep. In particular, this screen isolated translin (trsn), an mRNA/DNA binding protein that is highly conserved from flies to humans. Neuron specific knock-down or mutations in the trsn locus results in flies that fail suppress sleep during starvation, but have normal energy stores trsn is highly conserved across phyla and has a putative role in mammalian metabolic function. This proposal seeks to characterize the cellular and neuroanatomical function of trsn to determine how sleep and metabolic state are integrated. This work will define a critical link between metabolism and sleep regulation, providing new avenues for investigating sleep-feeding interactions that potently impact human health. Functional investigation of genes regulating sleep-metabolism interactions will provide the groundwork for understanding metabolic regulation of behavior and further our understanding of obesity, sleep disorders and diabetes.