The role of neural translin in metabolic control of sleep

神经转运蛋白在睡眠代谢控制中的作用

• 批准号: 9282472
• 负责人: Alex C Keene
• 金额: $ 28.89万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282472
• 关键词: Acetylcholine; Acute; Adult; Animals; Appetite Regulation; Behavior; Behavioral; Cells; Choline O-Acetyltransferase; DNA-Binding Proteins; Desire for food; Development; Diabetes Mellitus; Disease; Drosophila genus; Drosophila melanogaster; Failure; Food; Genes; Genetic; Genetic Processes; Glucose; Head; Health; Heart Atrium; Homeostasis; Human; Image; Insulin; Insulin Receptor; Investigation; Label; Link; Mammals; Measures; Messenger RNA; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic syndrome; Metabolism; Mutation; Nervous system structure; Neurons; Neuropeptides; Nutrient; Nutritional; Obesity; Pathology; Peptides; Phenocopy; Physiology; Population; Prevalence; Proxy; RNA interference screen; Rattus; Receptor Activation; Regulation; Role; Sleep; Sleep Disorders; Starvation; System; Testing; Transcriptional Regulation; Transgenic Organisms; Work; experimental study; feeding; fly; genetic approach; insulin signaling; knock-down; mutant; neuroregulation; pancreatic secretory trypsin inhibitor I; pressure; public health relevance; receptor function; relating to nervous system; response; sensor; sleep regulation; tool

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.

描述（由申请人提供）：睡眠、食欲和能量稳态的神经调节对于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。苍蝇和哺乳动物一样，可以根据营养需求有效调节睡眠。具体来说，苍蝇和哺乳动物会因饥饿而抑制睡眠，可能是为了引发寻找食物的行为。果蝇强大的遗传学可以精确表征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，揭示了睡眠代谢调节所需的众多目标。特别是，该筛选分离出了易位蛋白 (trsn)，这是一种从果蝇到人类高度保守的 mRNA/DNA 结合蛋白。神经元特异性敲除或 trsn 位点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。该提案旨在表征 trsn 的细胞和神经解剖功能，以确定睡眠和代谢状态如何整合。这项工作将定义新陈代谢和睡眠调节之间的关键联系，为研究有效影响人类健康的睡眠喂养相互作用提供新途径。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奠定基础，并进一步加深我们对肥胖、睡眠障碍和糖尿病的理解。