Molecular and neural mechanisms generating and synchronizing circadian rhythms

 描述（由申请人提供）：昼夜节律至关重要，因为它们使大多数生物体能够科普其环境中每天发生的物理和生态变化。事实上，他们对大多数身体功能进行计时，从基本的新陈代谢到行为，以便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，昼夜节律的破坏严重影响人类健康。情绪障碍与昼夜节律的不同步有关，例如，特定的癌症和胃肠道疾病在轮班工人中更常见。我们使用果蝇Drosophila melanogaster来研究昼夜节律的基本原理及其与昼夜周期的同步（夹带）。事实上，一个时钟如果因为不能对环境信号做出反应或者因为它的起搏器机制有缺陷而偏离了相位，那么它就没有适应价值，而且对健康有害。我们正在追求三个主要目标，利用果蝇遗传学，分子生物学和神经生物学的全部力量。我们的第一个目标是阐明光和温度周期，两个最重要的环境线索的昼夜夹带的分子机制。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奏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，夹带依赖于细胞自主分子机制和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，特别感兴趣的是确定mRNA加工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，这些基因表达的调节步骤对昼夜节律至关重要。然而，与昼夜节律的转录和翻译后调控相比，人们对昼夜节律mRNA代谢和翻译的调控机制知之甚少。我们希望我们的工作提供了一个综合的图片的机制产生，控制和同步果蝇的昼夜节律。重要的是，从果蝇到哺乳动物，昼夜节律的基本机制都非常保守。因此，我们预计，我们的工作也将证明对我们理解哺乳动物的昼夜节律很重要，因此可能最终影响我们治疗与昼夜节律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.