The role of neural translin in metabolic control of sleep

描述（申请人提供）：神经调节睡眠，食欲和能量稳态对动物的生存和严格的进化压力至关重要。睡眠失调与肥胖、糖尿病和代谢疾病密切相关。尽管与代谢和睡眠相关的疾病普遍存在，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。该提案将研究基因和神经元如何调节睡眠以响应新陈代谢的变化。和哺乳动物一样，苍蝇也能根据自身的营养需求有效地调节睡眠。具体来说，苍蝇和哺乳动物在饥饿时抑制睡眠，可能是为了启动寻找食物的行为。果蝇中强大的基因可以精确地描述调节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干扰筛选，发现了睡眠代谢调节所需的许多靶标。特别是，该筛选分离出了translin (trsn)，这是一种mRNA/DNA结合蛋白，从果蝇到人类都高度保守。trsn位点的神经元特异性敲除或突变导致果蝇在饥饿期间无法抑制睡眠，但具有正常的能量储存，trsn在整个门中高度保守，并且在哺乳动物代谢功能中具有假定的作用。本研究旨在描述trsn的细胞和神经解剖学功能，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-摄食相互作用提供新的途径。对调节睡眠-代谢相互作用的基因的功能研究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。

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.