The role of neural translin in metabolic control of sleep

描述(由申请人提供)：睡眠、食欲和能量平衡的神经调节对动物的生存和在严格的进化压力下至关重要。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很普遍，但调节这两个系统之间相互作用的神经和遗传过程尚不清楚。这项研究将研究基因和神经元如何调节睡眠以应对新陈代谢的变化。苍蝇和哺乳动物一样，会根据自己的营养需求来调节睡眠。具体地说，苍蝇和哺乳动物在饥饿时会抑制睡眠，这可能是为了启动觅食行为。果蝇中强大的遗传学允许精确描述调控行为和代谢过程的基因。我最近对1100多个基因进行了神经元特异性RNA干扰筛查，发现了睡眠代谢调节所需的许多靶点。特别是，这一筛选分离了翻译蛋白(Trsn)，这是一种从苍蝇到人类高度保守的mRNA/DNA结合蛋白。神经元特异性的trsn基因敲除或突变导致果蝇在饥饿期间无法抑制睡眠，但具有正常的能量存储，trsn在整个门中高度保守，并在哺乳动物的代谢功能中发挥可能的作用。这项建议试图确定trsn的细胞和神经解剖功能，以确定睡眠和代谢状态是如何整合的。这项工作将确定新陈代谢和睡眠调节之间的关键联系，为研究可能影响人类健康的睡眠-喂养相互作用提供新的途径。对调节睡眠-代谢相互作用的基因进行功能研究将为理解行为的代谢调节以及进一步了解肥胖、睡眠障碍和糖尿病提供基础。

DESCRIPTION (provided by applicant): 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.