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Balance of sleep and circadian metabolic switches in Drosophila

果蝇的睡眠平衡和昼夜代谢开关

基本信息

批准号：
10407604
负责人：
AMITA SEHGAL
金额：
$ 50.59万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407604
关键词：
Address Affect Behavior Therapy Biological Models Bolus Infusion Caloric Restriction Carbon Dioxide Cardiometabolic Disease Cells Circadian Dysregulation Circadian Rhythms Clinical Clinical Research Data Desegregation Diabetes Mellitus Dietary Intervention Drosophila genus Drosophila melanogaster Electronics Energy Intake Equilibrium Face Future Generations Genetic Glean Glucose Health High Fat Diet Human Impairment Injections Insulin Resistance Intervention Jet Lag Syndrome Label Light Link Lipids Malignant Neoplasms Mass Spectrum Analysis Measures Mechanics Mediating Metabolic Metabolic Diseases Metabolic Marker Metabolic Pathway Metabolic syndrome Metabolism Methods Modeling Molecular Mus Neurons Neurotransmitters Nutrient Nutritional Obesity Oxidation-Reduction Oxidative Stress Pathway Pathway interactions Peripheral Pharmacology Phenotype Physiological Population Research Resolution Risk Risk Factors Rodent Rodent Model Sleep Sleep Deprivation Sleeplessness Standardization Stress Study models System Testing Time Time-restricted feeding Tracer Transcript Unhealthy Diet Work cardiometabolism circadian dietary manipulation dietary restriction experimental study feeding flexibility fly in vivo innovation insight insulin signaling metabolic abnormality assessment metabolic rate molecular clock mutant neurochemistry response shift work temporal measurement

项目摘要

PROJECT SUMMARY Sleep loss is increasingly recognized as a significant risk factor in numerous metabolic diseases such as diabetes, obesity, metabolic syndrome, cancer, and cardiometabolic disorders. Clinical and model studies have confirmed negative metabolic effects of sleep loss. Intriguingly, sleep loss also dampens peripheral rhythms in human populations, which raises the question of whether the metabolic-sleep connection is mediated through circadian rhythms. Time-dependent analysis of metabolic changes has revealed large-scale oscillations in metabolite pools through the course of the circadian day in humans and other model systems such as rodents and flies. Disruption of the molecular clock, either genetically or through dietary intervention such as high-fat diet or mis-timed restricted feeding, causes insulin resistance and a lack of so-called `metabolic flexibility', phenotypes shared with sleep loss. We hypothesize that effects of reduced sleep on metabolism are mediated through changes in rhythms of energetic and redox metabolic pathways. One major limitation in gleaning mechanistic understanding of the sleep-circadian-metabolism connection is difficulty in measuring metabolic flux at different times of day in vivo. Our team has developed an innovative model of circadian flux using Drosophila melanogaster (fruit fly). Furthermore, dietary manipulations, such as time-restricted feeding in the active period or caloric restriction, maintain amplitudes in metabolic cycles in face of circadian disruption and have been associated with cardio-metabolic health in flies. In this proposal, we will exploit the genetic flexibility of D. melanogaster to test the above hypothesis in the following related but independent aims:  Aim 1: Determine the impact of sleep loss on metabolic rhythms. Impact: An impact of sleep loss on metabolic oscillations will clarify the approach towards understanding how circadian rhythms and sleep, each of which is currently studied independently, affect metabolism.  Aim 2: Determine if nutritional challenge exacerbates the metabolic effects of sleep loss in a time-of- day specific manner. Impact: These studies will provide direct mechanistic insights into the origin of metabolic imbalance which has only been inferred in studies to date. Future pharmacological or behavioral interventions can be targeted accordingly.  Aim 3: Determine if time-restricted feeding can mitigate effects of sleep deprivation on metabolism. Impact: Demonstration that dietary manipulation mitigates negative metabolic consequences of sleep loss has the potential for interventional applicability in at risk real-world human populations.

项目概要睡眠不足越来越被认为是许多代谢疾病的重要危险因素，例如如糖尿病、肥胖症、代谢综合征、癌症和心脏代谢疾病。临床和模型研究已经证实睡眠不足对代谢产生负面影响。有趣的是，睡眠不足也会抑制外周神经系统人类的节律，这就提出了一个问题：代谢与睡眠之间的联系是否存在？通过昼夜节律介导。代谢变化的时间依赖性分析揭示了大规模人类和其他模型系统在昼夜节律中代谢物池的振荡例如啮齿动物和苍蝇。通过遗传或饮食干预扰乱分子时钟例如高脂肪饮食或不合时宜的限制喂养，会导致胰岛素抵抗和所谓的缺乏 “代谢灵活性”，与睡眠不足共有的表型。我们假设睡眠减少会影响新陈代谢是通过能量和氧化还原代谢途径的节律变化来介导的。收集睡眠昼夜代谢机制的一个主要限制联系是测量体内一天中不同时间的代谢通量的困难。我们的团队开发了一个使用果蝇（果蝇）的昼夜节律变化创新模型。此外，饮食控制，例如活跃期的限时喂食或热量限制，维持代谢幅度昼夜节律紊乱的周期，并且与果蝇的心脏代谢健康有关。在这个根据建议，我们将利用黑腹果蝇的遗传灵活性来检验上述假设：相关但独立的目标：目标 1：确定睡眠不足对代谢节律的影响。影响：睡眠不足对代谢波动的影响将阐明如何理解睡眠不足的方法目前正在独立研究昼夜节律和睡眠，这两者都会影响新陈代谢。目标 2：确定营养挑战是否会加剧睡眠不足对代谢的影响日具体方式。影响：这些研究将为代谢失衡的起源提供直接的机制见解。迄今为止仅在研究中推断出。未来的药物或行为干预可以有针对性因此。目标 3：确定限时喂养是否可以减轻睡眠不足对新陈代谢的影响。影响：证明饮食控制可以减轻睡眠不足造成的负面代谢后果具有对现实世界中高危人群进行干预的潜力。