Molecular and neural mechanisms generating and synchronizing circadian rhythms

 描述(申请人提供)：昼夜节律是至关重要的，因为它们使大多数生物体能够应对其环境中每天发生的物理和生态变化。事实上，它们为大多数身体功能计时，从基本新陈代谢到行为，因此它们与一天中的时间同步和优化。由于其对生理和行为的深刻影响，昼夜节律的紊乱严重影响着人类的健康。例如，情绪障碍与昼夜节律同步缺陷有关，而特定的癌症和胃肠道疾病在倒班工人中更常见。我们正在使用果蝇黑腹果蝇来研究昼夜节律及其与昼夜周期同步(夹带)的基本原理。事实上，一个时钟如果因为不能对环境信号做出反应或起搏器机制有缺陷而出现不同步，就不会有适应价值，对健康也是有害的。我们正在追求三个主要目标，充分利用果蝇遗传学、分子生物学和神经生物学的力量。我们的第一个目标是阐明昼夜节律对光和温度循环的分子机制，这是两个最重要的环境线索。我们将在分子水平上确定昼夜节律起搏器如何接收和响应光和热输入，以及它们如何整合它们。我们的第二个目标是了解控制节律行为的昼夜神经网络如何检测、响应和整合各种环境线索。事实上，在大脑中，携带作用既依赖于细胞自主的分子机制，也依赖于昼夜神经元之间的相互作用，以使昼夜行为与昼夜周期同步。最后，我们的第三个目标是了解昼夜节律是如何在分子水平上产生的，尤其是确定mRNA的处理和翻译的控制如何有助于昼夜节律。确实有越来越多的证据表明，这些基因表达的调控步骤对昼夜节律至关重要。然而，与昼夜节律转录和翻译后控制相反，我对昼夜节律mRNA代谢和翻译的调控机制知之甚少。我们希望我们的工作能为果蝇产生、控制和同步昼夜节律的机制提供一幅完整的图景。重要的是，昼夜节律的基本机制在动物身上保存得非常好，从果蝇到哺乳动物。因此，我们预计，我们的工作对我们理解哺乳动物的昼夜节律也很重要，因此可能最终影响我们治疗与生物钟紊乱相关的疾病的能力。

 DESCRIPTION (provided by applicant): Circadian rhythms are critically important, since they enable most organisms to cope with the physical and ecological changes occurring daily in their environment. Indeed, they time most bodily functions, from basic metabolism to behavior, so that they are synchronized and optimized with the time of day. Because of their profound impact on physiology and behavior, disruption of circadian rhythms seriously impact human health. Mood disorders are linked to defective synchronization of circadian rhythms, and specific cancers and gastro-intestinal diseases are more frequent in shift workers, for example. We are using the fruit fly Drosophila melanogaster to study the fundamental principles underlying circadian rhythms and their synchronization (entrainment) to the day/night cycle. Indeed, a clock that drifts out of phase because it cannot respond to environmental cues or because its pacemaker mechanism is defective would have no adaptive value and be detrimental to health. We are pursuing three major objectives, using the full power of Drosophila genetics, molecular biology and neurobiology. Our first goal is to elucidate the molecular mechanisms of circadian entrainment to light and temperature cycles, the two most important environmental cues. We will determine at the molecular level how circadian pacemakers receive and respond to photic and thermal inputs, and how they integrate them. Our second objective is to understand how the circadian neural network controlling rhythmic behaviors detects, responds and integrates various environmental cues. Indeed, in the brain, entrainment relies both on cell-autonomous molecular mechanisms and interactions between circadian neurons to synchronize circadian behaviors with the day/night cycle. Finally, our third objective is to understand how circadian rhythms are generated at the molecular level, with a particular interest in determining how the control of mRNA processing and translation contributes to circadian rhythms. There is indeed growing evidence that these regulatory steps of gene expression are critical for circadian rhythms. However, in contrast to circadian transcriptional and post-translational control, little i known about the mechanisms regulating circadian mRNA metabolism and translation. We expect our work to provide an integrative picture of the mechanisms generating, controlling and synchronizing circadian rhythms in fruit flies. Importantly, the basic mechanisms underlying circadian rhythms are remarkably well conserved in animals, from Drosophila to mammals. We therefore anticipate that our work will also prove important for our understanding of mammalian circadian rhythms, and might thus ultimately impact our ability to treat diseases associated with disrupted circadian clocks.