The role of RNA binding proteins in the control of Drosophila circadian rhythms

RNA结合蛋白在果蝇昼夜节律控制中的作用

• 批准号: 8368915
• 负责人: Patrick Emery
• 金额: $ 31.54万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-06 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8368915
• 关键词: Advanced Sleep Phase Syndrome; Affect; Animal Model; Animals; Attention; Behavior; Binding; Biological; Brain; Cell physiology; Circadian Rhythms; Communication; Control Animal; Cyanobacterium; Data; Disease; Drosophila genus; Enhancers; Ensure; Feedback; Gene Expression; Gene Expression Regulation; Genes; Genetic; Goals; Homologous Gene; Human; Image; Insecta; Level of Evidence; Life; Mammals; Mediating; Medical; Messenger RNA; Metabolism; MicroRNAs; Molecular; Mood Disorders; Mutate; Neurodegenerative Disorders; Neurons; Neuropeptides; Pacemakers; Pathway interactions; Patients; Periodicity; Phenotype; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiology; Play; Post-Translational Regulation; Protein Biosynthesis; Proteins; RNA Interference; RNA-Binding Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Sleep Disorders; Solid; Spinocerebellar Ataxias; Testing; Time; Transcription Coactivator; Transcription Repressor/Corepressor; Translational Regulation; Translations; Work; base; circadian pacemaker; fly; mRNA Stability; neural circuit; novel; plant fungi; promoter; psychologic; receptor; suprachiasmatic nucleus; transcription factor

DESCRIPTION (provided by applicant): Circadian rhythms are critically important for most animals, because they ensure that their physiology, metabolism and behavior is properly adapted to and synchronized with the day/night cycle. Circadian rhythms are generated in animals by a well-characterized transcriptional feedback loop. A set of kinases and phosphatases is responsible for the post-translational control of the transcription factors engaged in this loop. The role of intermediate levels of regulation such as mRNA stability and translational control have so far received little attention, although there is increasing evidence that such regulatory mechanisms do affect circadian rhythms. Our goal is to understand the role played by RNA binding proteins in the control of Drosophila circadian behavior. We will focus on GW182 and ATX2. Indeed, our preliminary data show that these two RNA binding proteins play crucial circadian functions. ATX2 regulates the pace of the circadian pacemaker, while GW182 is part of the PDF/PDFR signaling pathway that synchronizes brain circadian neurons. With our first aim, we will precisely define the circadian function of GW182 and determine how it interacts with the PDFR pathway. With our second aim, we will determine by which molecular mechanisms GW182 affects circadian behavior. Finally, with our third aim, we will determine the exact role of ATX2 in the circadian pacemaker, and the mechanisms underlying its circadian function. Together, these three aims will reveal completely novel mechanisms controlling circadian rhythms. Our work will most likely have important implications for our understanding of mammalian and human circadian rhythms. Indeed, both ATX2 and GW182 are evolutionary conserved molecules involved in conserved circadian pathways: the circadian molecular pacemaker is remarkably similar in mammals and Drosophila, while the PDF/PDFR signaling pathway is the functional and molecular homolog of the mammalian VIP/VIPR pathway, which synchronizes circadian neurons in the suprachiasmatic nucleus. Disrupted circadian rhythms are responsible for important psychological and somatic ailments in humans, particularly in shift worker and in patients with specific mood and sleep disorders. Our work should thus ultimately help understanding of the biological bases of these diseases. By understanding the cellular function of ATX2 in the context of circadian rhythms, our work should also reveal novel mechanisms by which ATX2 controls gene expression. Our work might thus impact our understanding of the mechanisms underlying neurodegenerative diseases, since ATX2 is implicated in spinocerebellar ataxia. PUBLIC HEALTH RELEVANCE: Disruptions of circadian rhythms - which control our daily behavior and physiology - are responsible for various somatic and psychological diseases, for example in shift workers and in patients affected with specific sleep and mood disorders. Our work, focused on the role of RNA binding proteins in the control of Drosophila circadian rhythms, will reveal novel regulatory mechanisms controlling circadian clocks. Since the mechanisms underlying circadian rhythms are remarkably similar in Drosophila and mammals, our work should help understanding the biological bases of circadian rhythm-related diseases.

描述（由申请人提供）：昼夜节律对大多数动物至关重要，因为它们确保它们的生理、代谢和行为适当地适应昼夜循环并与之同步。动物的昼夜节律是由一个特征明显的转录反馈回路产生的。一组激酶和磷酸酶负责翻译后控制参与该环的转录因子。尽管有越来越多的证据表明这种调节机制确实影响昼夜节律，但中间水平调控（如mRNA稳定性和翻译控制）的作用迄今为止很少受到关注。我们的目标是了解RNA结合蛋白在果蝇昼夜节律行为控制中的作用。我们会专注于GW182和ATX2。事实上，我们的初步数据表明，这两种RNA结合蛋白起着至关重要的昼夜节律功能。ATX2调节昼夜节律起搏器的速度，而GW182是同步大脑昼夜节律神经元的PDF/PDFR信号通路的一部分。我们的第一个目标是精确定义GW182的昼夜节律功能，并确定它如何与PDFR通路相互作用。我们的第二个目标是确定GW182影响昼夜行为的分子机制。最后，在我们的第三个目标中，我们将确定ATX2在昼夜节律起搏器中的确切作用及其昼夜节律功能的机制。总之，这三个目标将揭示控制昼夜节律的全新机制。我们的工作很可能会对我们理解哺乳动物和人类的昼夜节律产生重要影响。事实上，ATX2和GW182都是参与保守昼夜节律通路的进化保守分子：哺乳动物和果蝇的昼夜节律分子起搏器非常相似，而PDF/PDFR信号通路与哺乳动物的VIP/VIPR信号通路在功能和分子上是同源的，后者同步视交叉上核的昼夜节律神经元。昼夜节律紊乱是人类重要的心理和躯体疾病的原因，特别是在轮班工作者和患有特定情绪和睡眠障碍的患者中。因此，我们的工作最终应该有助于了解这些疾病的生物学基础。通过了解ATX2在昼夜节律背景下的细胞功能，我们的工作也应该揭示ATX2控制基因表达的新机制。因此，我们的工作可能会影响我们对神经退行性疾病机制的理解，因为ATX2与脊髓小脑性共济失调有关。