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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发展到适当地调整生物过程以适应不断变化的24小时环境。果蝇昼夜运动活动节律的遗传分析揭示了转录反馈回路作为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是由蛋白质磷酸化和随后的降解决定的，时钟分量的表达式，例如周期（PER）。在果蝇中，光能够重置这些振荡器部分地通过时钟组件TIMELESS（TIM）的降级。值得注意的是，这些时钟在动物中保存。昼夜节律钟也使适当的适应季节性变化，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，机械理解这两种途径如何合作，以介导光反应，包括改变光周期，是动物所缺乏的。这里发现了一种新颖的时钟组件，再生肝磷酸酶-1（PRL-1），对光介导的重置和设置也很重要在不同季节光周期下的行为阶段。这项研究建议利用发现 PRL-1了解生物钟如何整合光信息以驱动适当的定时行为。它将专门解决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介导PRL-1效应。这些研究利用了核心时钟的发现在光周期依赖性行为中具有新作用的组分。此外，还充分利用了果蝇系统的核心包括保守的时钟机制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流式细胞仪分选和分离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见解以产生定时行为。