Mechanisms of Circadian Clock Output

昼夜节律时钟输出机制

• 批准号: 6999745
• 负责人: Paul H Taghert
• 金额: $ 29.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6999745
• 关键词: Drosophilidae; Xenopus; arthropod genetics; biological signal transduction; circadian rhythms; gene expression; invertebrate locomotion; microarray technology; neural transmission; neurogenetics; neuropeptides; transcription factor

DESCRIPTION (provided by applicant): We are interested in signaling mechanisms used by circadian pacemaker neurons to organize daily locomotor behavior. There has been tremendous progress in recent years in defining the molecular basis of the cell autonomous clockwork mechanism that underlies circadian timekeeping. That definition has permitted the identification of the primary circadian clock neurons within the brain. In turn, that has presented the opportunity to re-examine fundamental issues concerning the neural basis of behavior. This research program features cellular, molecular and genetic techniques to understand how signals are passed from the primary pacemakers to responsive neurons. Previously we showed that the neuropeptide PDF is the principal circadian transmitter in Drosophila. Genetic evidence indicates it is the most important signal used by the primary clock cells (the LN-v neurons). We will extend that information by performing experiments that are designed to ask where and when PDF signals circadian time within the brain. Further, we will identify and characterize the receptor(s) for PDF. Definition of the PDF receptor will permit a description of which neural elements and which circuits respond to the circadian transmitter. We can also begin to ask what are the long-term consequences (signal transduction pathways) that are modulated as a result of PDF receptor activation. Because circadian signaling occurs on such a long time base (many hours), we hypothesize that PDF signaling may include transcriptional regulation. We have identified several genes whose expression levels are pdf-dependent and which cycle on a daily basis. We propose now to demonstrate their role as PDF targets for the mediation of circadian signaling. Finally, we have performed an extensive genome-wide microarray screen for circadian gene expression in the Drosophila head. We have identified 22 circadian genes, of which 15 are novel in the context of circadian biology. We hypothesize that most of these circadian genes participate in circadian output mechanisms, and propose experiments to address this possibility

描述（由申请人提供）：我们对昼夜节律起搏器神经元使用的信号传导机制感兴趣，以组织日常运动行为。近年来，在定义了昼夜节律计时的细胞自动发条机制的分子基础方面取得了巨大进展。该定义允许鉴定大脑中的主要昼夜节律神经元。反过来，这为重新检查有关行为神经基础的基本问题提供了机会。该研究计划具有细胞，分子和遗传技术，以了解信号如何从主要的起搏器传递到反应性神经元。以前，我们表明神经肽PDF是果蝇中的主要昼夜节律发射器。遗传证据表明，它是主要时钟细胞（LN-V神经元）使用的最重要的信号。我们将通过执行旨在询问PDF在大脑中的昼夜节时间的何时以及何时何时询问的实验来扩展这些信息。此外，我们将确定并表征PDF的受体。 PDF受体的定义将允许描述哪些神经元件以及哪些电路对昼夜节律发射器响应。我们还可以开始询问由于PDF受体激活而调节的长期后果（信号转导途径）。由于昼夜节信号传导发生在如此长的碱基（很多小时）上，因此我们假设PDF信号传导可能包括转录调控。我们已经确定了几个基因，其表达水平依赖于PDF，并且每天哪个循环。我们现在建议证明它们是昼夜节信号介导的PDF目标的作用。最后，我们对果蝇头的昼夜节律表达进行了广泛的全基因组微阵列筛选。我们已经确定了22个昼夜节律基因，其中15个在昼夜节律生物学的背景下是新颖的。我们假设这些昼夜节律中的大多数都参与昼夜节律的输出机制，并提出了实验以解决这种可能性