The role of Nf1 in sleep-dependent regulation of metabolic function

Nf1 在睡眠依赖性代谢功能调节中的作用

• 批准号: 10317548
• 负责人: Alex C Keene
• 金额: $ 46.52万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317548
• 关键词: Acute; Adult; Affect; Animals; Biological Assay; Cells; Collaborations; Data; Development; Diabetes Mellitus; Disease; Drosophila genus; Epidemiology; FRAP1 gene; Genes; Genetic; Health; Homeostasis; Human; Impairment; Indirect Calorimetry; Investigation; Learning; Light; Link; Mammals; Measurement; Measures; Mediating; Metabolic; Metabolic syndrome; Metabolism; Modeling; Molecular; Mutation; NF1 gene; NF1 mutation; Nervous system structure; Neurons; Obesity; Physiological; Point Mutation; Process; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Stages; Sleep disturbances; Structure; Symptoms; System; Tertiary Protein Structure; Testing; Transgenes; Variant; Work; experimental study; fly; genetic approach; human disease; insight; knock-down; metabolic rate; mutant; neural circuit; neuromechanism; neuroregulation; novel; ras GTPase-Activating Proteins; relating to nervous system; sleep regulation; tool

Project Summary Neural regulation of sleep and metabolic homeostasis are critical to many aspects of human health. Despite extensive epidemiological evidence linking sleep dysregulation with obesity, diabetes, and metabolic syndrome, little is known about the neural and molecular basis for the integration of sleep and metabolic state. The genetic and functional basis of sleep is highly conserved from fruit flies to mammals. While the application of genetic approaches in flies have been used to identify novel genes and neural circuit mechanisms regulating sleep, the field has predominantly focused on sleep duration, rather than the physiological effects of sleep. This proposal employs a novel assay for simultaneously measuring sleep and metabolic rate in single flies. Preliminary data reveals that mutation of Neurofibromin 1 (Nf1), a gene that has been linked to sleep and metabolic dysregulation in humans, abolishes sleep-dependent modulation of metabolic rate in flies. The proposed experiments seek to identify the neurons required for sleep-metabolism interactions and determine the effects of Nf1 on the activity of neural circuits regulating sleep and metabolic function. Further, genetic experiments will be performed to identify the protein domains within NF1, and downstream signaling pathways, that are required for sleep-metabolism interactions. The completion of this work will yield insights into the cellular and neural circuit basis for the integration of sleep and metabolic rate, and establish flies as a model for investigating these interactions. Given the robust conservation of sleep and metabolism between flies and mammals, these results will provide a platform for investigation of how these processes are regulated, with the potential to provide insight into the association between sleep loss and metabolism-related disease.

项目概要 睡眠和代谢稳态的神经调节对人类健康的许多方面都至关重要。尽管 大量流行病学证据表明睡眠失调与肥胖、糖尿病和代谢有关 对于睡眠和代谢状态整合的神经和分子基础，我们知之甚少。 从果蝇到哺乳动物，睡眠的遗传和功能基础高度保守。在申请的同时 果蝇的遗传方法已被用来识别新的基因和调节神经回路的机制 睡眠，该领域主要关注睡眠持续时间，而不是睡眠的生理影响。 该提案采用了一种新颖的测定方法来同时测量单只果蝇的睡眠和代谢率。 初步数据显示，神经纤维蛋白 1 (Nf1) 的突变，该基因与睡眠和睡眠有关 人类的代谢失调，消除了果蝇的睡眠依赖性代谢率调节。这 拟议的实验旨在识别睡眠代谢相互作用所需的神经元并确定 Nf1 对调节睡眠和代谢功能的神经回路活动的影响。此外，遗传 将进行实验来识别 NF1 内的蛋白质结构域和下游信号通路， 这是睡眠与新陈代谢相互作用所必需的。这项工作的完成将带来对 睡眠与代谢率整合的细胞和神经回路基础，并建立果蝇模型 用于研究这些相互作用。鉴于果蝇和果蝇之间睡眠和新陈代谢的稳健保持 哺乳动物，这些结果将为研究这些过程是如何调节的提供一个平台， 有望深入了解睡眠不足与代谢相关疾病之间的关系。