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Molecular Mechanisms Integrating Circadian Timing and Photic Signaling

整合昼夜节律和光信号传导的分子机制

基本信息

批准号：
10334518
负责人：
Ravi Allada
金额：
$ 34.56万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10334518
关键词：
Address Affect Alleles Animals Automobile Driving Behavior Behavioral Biological Process Cell Line Cells Communication Coupling Data Dependence Disease Drosophila genus Environment Feedback Genetic Genetic Transcription Hour Impairment Jet Lag Syndrome Length Light Literature Mediating Modeling Molecular Molecular Genetics Motor Activity Neurons Pacemakers Pathway interactions Periodicity Phase Phenotype Phosphorylation Phosphotransferases Photoperiod Photoreceptors Physiologic pulse Protein Dephosphorylation Publishing Regulation Research Role Signal Pathway Signal Transduction Site Sleeplessness Speed System Testing Time Visual Work cell type circadian circadian pacemaker day length gene function genetic analysis genetic manipulation genetic resource insight intercellular communication light effects molecular clock mutant neural network architecture nonvisual photoreceptor novel phosphatase of regenerating liver relating to nervous system response shift work

项目摘要

Project Summary Circadian clocks have evolved to appropriately align biological processes to the changing 24 h environment. Genetic analyses of circadian locomotor activity rhythms in the fruit fly Drosophila have revealed transcriptional feedback loops as the core organizing principle of circadian clocks. Yet the pace of these circadian feedback loops is largely determined by protein phosphorylation and subsequent degradation, driving rhythmic expression of clock components such as PERIOD (PER). In Drosophila, light is able to reset these oscillators in part via degradation of the clock component TIMELESS (TIM). Remarkably, these clocks are highly conserved among animals. Circadian clocks also enable the appropriate adaptation to seasonal changes in day length or photoperiod. Yet while much is known about both core clock and photic input mechanisms, a mechanistic understanding of how these two pathways collaborate to mediate responses light, including changing photoperiod, is lacking in animals. Here a novel clock component has been discovered, the phosphatase of regenerating liver-1 (PRL-1), that is also important for light mediated resetting and setting behavioral phase under varying seasonal photoperiod. This research proposes to leverage the discovery of PRL-1 to understand how the circadian clock integrates light information to drive appropriately timed behavior. It will specifically address the neuronal basis of PRL-1 function including the role in specific photoreceptor pathways, its function in autonomous and coupling neuronal oscillators, and the role of the light and clock regulated clock component TIM in mediating PRL-1 effects. These studies exploit the discovery of a core clock component with a novel role in photoperiod-dependent behavior. In addition, full advantage is taken of the Drosophila system, including the conservation of the core clock machinery and clock neural network architecture as well as extensive molecular genetic resources to examine gene function in the whole animal. This research also leverages the ability to quantitatively examine molecular oscillations in FACS sorted and intact neurons. This work could provide insights into how circadian clocks integrate environmental information to yield timed behavior.

项目摘要生物钟已经进化，使生物过程与不断变化的24小时环境相适应。果蝇昼夜活动节律的遗传分析揭示了转录反馈环是生物钟的核心组织原则。然而，这些昼夜节律反馈的速度环在很大程度上由蛋白质磷酸化和随后的降解决定，驱动节律时钟分量的表达式，如周期(PER)。在果蝇中，光能够重置这些振荡器部分地通过时钟分量无时间(TIM)的降级。值得注意的是，这些时钟高度精确在动物中保存。生物钟也能适当地适应季节变化日长或光周期。然而，虽然对核心时钟和光输入机制都有很多了解，但一个对这两条通路如何协同调节光反应的机械性理解，包括改变光周期，是动物所缺乏的。这里发现了一种新的时钟组件，即再生肝磷酸酶-1(PRL-1)，这对光介导的重置和定形也很重要不同季节光周期下的行为阶段。这项研究建议利用发现的 PRL-1，以了解生物钟如何整合光信息来驱动适当的定时行为。它将专门讨论PRL-1功能的神经元基础，包括在特定光感受器中的作用通路，其在自主和耦合神经元振荡器中的功能，以及光和时钟的作用调节时钟成分TIM在调节PRL-1效应中的作用。这些研究利用了核心钟的发现在光周期依赖行为中具有新作用的组件。此外，还充分利用了果蝇系统，包括守恒的核心时钟机械和时钟神经网络结构以及广泛的分子遗传资源，以检查整个动物的基因功能。这项研究还利用了定量检查FAC中分子振荡的能力，完整的神经元。这项工作可以为生物钟如何整合环境信息提供洞察。以产生计时行为。