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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.

项目概要生物钟已经发展到可以根据不断变化的 24 小时环境适当调整生物过程。果蝇昼夜运动活动节律的遗传分析揭示了转录反馈循环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很大程度上由蛋白质磷酸化和随后的降解决定，驱动有节奏的时钟组件的表达式，例如 PERIOD (PER)。在果蝇中，光能够重置这些振荡器部分是由于时钟组件 TIMELESS (TIM) 的退化。值得注意的是，这些时钟非常动物间保存。昼夜节律时钟还能够适当适应季节变化日长或光周期。然而，尽管人们对核心时钟和光输入机制了解很多，但对这两种途径如何协作介导光反应的机制理解，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)，对于光介导的重置和设置也很重要不同季节光周期下的行为阶段。这项研究建议利用以下发现 PRL-1 了解生物钟如何整合光信息来驱动适当的定时行为。它将专门探讨 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组件 TIM 调节 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成分。此外，还充分利用了果蝇系统，包括核心时钟机制和时钟神经网络的保护结构以及广泛的分子遗传资源来检查整个动物的基因功能。这项研究还利用了 FACS 中定量检查分子振荡的能力完整的神经元。这项工作可以深入了解生物钟如何整合环境信息产生定时行为。