Neural and Molecular Mechanisms underlying Sleep and Metabolic Rhythms

项目摘要/摘要 昼夜节律是行为和生理上的24小时振荡，它被保存在 地球上几乎所有形式的生命，使有机体能够适应地球的昼夜周期。 生物钟的失调与许多人类疾病有关，包括 糖尿病、肥胖症和神经退行性疾病。我研究的长期目标是 了解生物钟是如何调节的，以及它们的干扰如何导致人类 病理学。在接下来的五年里，我建议研究神经和分子基础 昼夜节律对两种外部信号的反应：温度和食物。昼夜节律 在恒定的条件下是自我维持的，但它们必须受到外部因素的影响/调整 光线、温度或食物等信号每天循环，以保持准确的24小时周期。过去时 开创性的工作揭示了主要的时钟组件和潜在的机制 光夹带和睡眠-觉醒节律。然而，神经和分子机制通过 哪些其他外部提示，温度和有节奏的食物摄入，缠绕着时钟和 相关的投入和产出机制在很大程度上仍未得到探索。我最近取得了一项 理解昼夜节律时钟神经元如何处理温度信息以 调节睡眠-觉醒节律。在这个提议中，我试图研究神经和分子 果蝇温度夹带和食物夹带的机制 黑腹蛇是一种强大的模式生物，因为它的时钟与人类相似，高度保守 以及一流的遗传和行为工具。具体地说，我将首先阐明新的 温度输入途径，并揭示支配 温度循环下的睡眠-觉醒节律。在这些努力中，我将使用多学科 一种将新型仪器与强大的遗传、分子、行为 和实时成像方法。接下来，为了阐明食物夹带的机制，我 将利用我最近开发的新的高分辨率热量测量和其他工具 第一次使控制进食时间和监测成为可能 个体生物体的代谢节律。这项工作将揭示根本和重要的 对昼夜节律的新见解，预计将在进化上高度保守。 此外，这项工作可以有几个实际好处，因为它可能为 开发以时钟机械为目标的新战略来治疗疾病。

PROJECT SUMMARY/ABSTRACT Circadian rhythms are 24-hour oscillations in behavior and physiology that are conserved in almost all forms of life on earth, enabling organisms to adapt to earth’s diurnal cycles. Dysregulation of circadian clocks has been linked to many human pathologies, including diabetes, obesity and neurodegenerative diseases. The long-term goal of my research is to understand how circadian clocks are regulated and how their disruption leads to human pathologies. In the next five years, I propose to investigate the neural and molecular basis of circadian regulation in response to two external cues: temperature and food. Circadian rhythms are self-sustained in constant conditions, but they have to be entrained/adjusted by external cues such as light, temperature or food cycles daily to maintain a precise 24-hour period. Past pioneering work has uncovered the major clock components and the mechanisms underlying light entrainment and sleep-wake rhythms. However, the neural and molecular mechanisms by which other external cues, temperature and rhythmic food intake, entrain the clock and the related input and output mechanisms remain largely unexplored. I recently achieved a breakthrough in understanding how circadian clock neurons process temperature information to regulate sleep-wake rhythms. In this proposal, I seek to investigate the neural and molecular mechanisms underlying temperature entrainment and food entrainment in Drosophila melanogaster, a powerful model organism as it has a highly conserved clock similar to humans along with superb genetic and behavioral tools. Specifically, I will first elucidate new temperature input pathways and reveal the neural and molecular mechanisms that govern sleep-wake rhythms under temperature cycles. In these efforts, I will use a multidisciplinary approach combining novel instrumentation along with powerful genetic, molecular, behavioral, and live imaging approaches. Next, to elucidate the mechanisms underlying food entrainment, I will leverage novel high-resolution calorimetry and other tools that I recently developed that makes it possible, for the first time, to both control the timing of food intake and monitor metabolic rhythms from individual organisms. This work will uncover fundamental and important new insights into circadian regulation which are expected to be highly evolutionarily conserved. Further, this work can have several practical benefits as it may provide new opportunities for the development of novel strategies to target clock machinery to treat diseases.