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

项目摘要 睡眠和代谢动态平衡的神经调节对人类健康的许多方面都是至关重要的。尽管 广泛的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，人们知之甚少。 从果蝇到哺乳动物，睡眠的基因和功能基础都高度保守。当应用程序 已被用来识别新的基因和神经回路调节机制 关于睡眠，该领域主要关注睡眠持续时间，而不是睡眠的生理影响。 这项建议采用了一种新的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，一种与睡眠和 人类的代谢失调，取消了对果蝇代谢率的睡眠依赖的调节。这个 拟议的实验试图确定睡眠-新陈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，基因 将进行实验以确定NF1内的蛋白质结构域和下游信号通路， 这是睡眠-新陈代谢相互作用所必需的。这项工作的完成将使人们对 以细胞和神经回路为基础整合睡眠和代谢率，并建立苍蝇模型 来研究这些相互作用。考虑到苍蝇和苍蝇之间睡眠和新陈代谢的强健保护 这些结果将为研究这些过程是如何调控的提供一个平台， 有可能深入了解睡眠不足和新陈代谢相关疾病之间的联系。

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.