Molecular and cellular mechanisms underlying circadian rhythms and sleep in Drosophila

摘要： 地球上的环境正在有节奏地变化，有机体需要适应和预测 这些周期性变化。对于我们人类来说，最引人注目和最具影响力的环境周期是 昼夜交替，我们围绕它来组织我们的活动。例如，我们通常工作和吃饭 白天，晚上睡得更好。实际上，我们的新陈代谢、生理和行为都是 由被称为生物钟的细胞内分子定时器控制，它优化了我们大多数身体功能 随着时间的推移。当这些生物钟被打乱时，例如在轮班工人中，发病率 癌症、代谢性疾病和情绪障碍的风险增加。生物钟存在于大多数 生物，以及在蓝藻、植物、真菌和哺乳动物中使用有效的遗传易处理模型 揭示了昼夜节律的基本原理。在所有真核生物中，转录反馈 由翻译后修饰调控的环是分子生物钟的核心。 果蝇已被证明是研究昼夜节律的一个特别有效的模型。 节律，以及在果蝇中发现的分子和神经机制被发现尤其 在哺乳动物中保存得很好。果蝇也是研究睡眠的一个非常有效的系统，睡眠是昼夜节律输出的关键。 我们的长期目标是详细了解果蝇昼夜节律是如何产生的，以及如何 它们与昼夜周期同步。最近，我们还研究了睡眠是如何被控制的 果蝇。我们在这里建议解决三个关键问题。首先，我们的目标是全面确定如何 转录后调控机制控制着昼夜节律。事实上，虽然昼夜节律转录 和翻译后控制已经被详细描述，昼夜节律的调节在 对信使核糖核酸的加工和翻译水平仍知之甚少。第二，我们的目标是了解 温度补偿现象。此属性确保昼夜节律时钟的周期为 对环境温度不敏感，因此这些生物定时器必须具有适应性 价值。然而，昼夜温度补偿是如何实现的仍不清楚。第三，我们的目标是 揭示神经胶质细胞调节睡眠的机制，重点是神经胶质转运蛋白。事实上，胶质细胞是 作为果蝇和哺乳动物神经睡眠回路的重要调节器。 这三个创新目标应该决定性地促进我们对昼夜节律和 睡在果蝇身上。考虑到生物钟和睡眠背后的机制的保守性，以及 它们对包括人类在内的动物的福祉和生存起着至关重要的作用，我们希望我们的 这项工作将产生广泛的影响，包括对人类健康的影响。

Summary: The environment on Earth is rhythmically changing, and organisms need to adapt to and anticipate these cyclical variations. For us humans, the most striking and impactful environmental cycle is the alternance of day and night, and we organize our activities around it. For example, we usually work and eat during the day, and sleep preferentially at night. Actually, our metabolism, physiology and behavior are all controlled by intracellular molecular timers called circadian clocks, that optimize most of our bodily functions with the time-of-day. When these biological clocks are disrupted, for example in shift workers, the incidence of cancers, metabolic diseases and mood disorders is increased. Circadian clocks are present in most organisms, and the use of potent genetically-tractable models in cyanobacteria, plants, fungi and mammals has shed light on the basic principles underlying circadian rhythms. In all eukaryotes, transcriptional feedback loops modulated by post-translational modifications are at the core of the molecular circadian clock. Drosophila melanogaster has proved to be a particularly potent model for the study of circadian rhythms, and the molecular and neural mechanisms uncovered in fruit flies have been found to be particularly well conserved in mammals. Drosophila is also a very efficient system to study sleep, a key circadian output. Our long-term goals are to understand in detail how Drosophila circadian rhythms are generated and how they are synchronized with the day/night cycle. More recently, we have also studied how sleep is controlled in fruit flies. We propose here to tackle three critical questions. First, we aim to determine comprehensively how post-transcriptional regulatory mechanisms control circadian rhythms. Indeed, while circadian transcriptional and post-translational controls have been characterized in detail, the regulation of circadian rhythms at the mRNA processing and translational levels remains poorly understood. Second, we aim to understand the phenomenon of temperature compensation. This property ensures that the period of circadian clocks is insensitive to ambient temperature and is therefore necessary for these biological timers to be of adaptative value. However, how circadian temperature compensation is achieved remains unclear. Third, we aim to uncover the mechanisms by which glia regulate sleep, with a focus on glial transporters. Indeed, glia is emerging as an important modulator of neural sleep circuits in fruit flies and mammals. These three innovative aims should decisively advance our understanding of circadian rhythms and sleep in Drosophila. Given the conservation of the mechanisms underlying circadian clocks and sleep, and the essential role they play for the well-being and survival of animals including humans, we expect that our work will have broad implications, including for human health.