CAREER: Circadian Control and Integration of Feeding and Metabolic Rhythms in Drosophila

职业：果蝇的昼夜节律控制以及摄食和代谢节律的整合

• 批准号: 1942167
• 负责人: Daniel Cavanaugh
• 金额: $ 83.09万
• 依托单位: Loyola University of Chicago
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1942167&HistoricalAwards=false
• 关键词: CAREER; Circadian; Control; Integration; Feeding

Organisms exhibit ~24-hour (circadian) rhythms in behavioral and physiological processes that depend on the presence of dedicated clock cells in the brain that keep time through a molecular clock that maintains daily rhythms of gene expression. In addition, molecular clocks are present in most peripheral tissues, where they serve tissue-specific functions. Together, these make up an extended clock network that synchronizes behavioral and physiological processes with the external environment and organizes them with respect to one another. For example, the circadian system generates rhythms in feeding behaviors such that feeding occurs at optimal times of day, and concurrently upregulates metabolic pathways in anticipation of increased food intake. Proper circadian organization is essential for organismal fitness, but the cellular and molecular mechanisms through which circadian rhythms are generated and integrated across multiple clock-containing tissues are unknown. To that end, experiments outlined in this project will use the powerful model organism of the fruit fly, Drosophila melanogaster, to identify neuronal pathways through which clock cells establish circadian rhythms of feeding behavior and to further delineate how feeding rhythms are coordinated with peripheral metabolic rhythms. These experiments will be conducted in collaboration with postdoctoral and undergraduate researchers in the lab who will also serve as mentors for a summer high school internship program that will expand participation to groups traditionally underrepresented in the sciences.An understanding of the manner through which the circadian system modulates behavioral outputs and coordinates these with physiological rhythms requires analysis of novel circadian endpoints in addition to rest and activity, which has thus far been the focus of most circadian research. Objective 1 will use a newly-developed feeding monitor to determine the cellular logic through which the central clock regulates feeding rhythms. To determine whether distinct central clock mechanisms control feeding and locomotor activity rhythms, period and strength of feeding rhythms will be measured following genetic manipulations that alter molecular clock function or neuronal activity in discrete clock cell populations. Objective 2 will investigate downstream output pathways through which feeding rhythms are produced. To enact behavioral rhythms, circadian information must be transmitted across output pathways to brain areas that regulate behaviors. The Cavanaugh laboratory recently implicated SIFa peptide-expressing neurons as a component of the circadian output pathway controlling feeding. To continue to trace the circadian feeding circuit, an RNA interference-based behavioral screen will be conducted to identify cells in which the SIFa receptor must be present for normal feeding rhythms. Finally, Objective 3 will investigate how feeding and metabolic rhythms are coordinated by the clock network. The fat body is a peripheral clock tissue that serves metabolic functions. A combined transcriptomic and metabolomic approach will be employed to determine how loss of SIFa signaling or selective molecular clock abrogation in the brain or fat body affects fat body gene oscillations and whole-animal metabolite abundance.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

生物体在行为和生理过程中表现出约24小时（昼夜）节律，这取决于大脑中存在专门的时钟细胞，这些细胞通过维持基因表达每日节律的分子钟保持时间。此外，分子钟存在于大多数外周组织中，在那里它们发挥组织特异性功能。这些共同构成了一个扩展的时钟网络，将行为和生理过程与外部环境联系起来，并将它们相互组织起来。例如，昼夜节律系统在进食行为中产生节律，使得进食发生在一天中的最佳时间，并且同时上调代谢途径以预期增加的食物摄入。适当的昼夜节律组织对于生物体的适应性至关重要，但是昼夜节律产生和整合在多个包含时钟的组织中的细胞和分子机制尚不清楚。为此，该项目中概述的实验将使用果蝇的强大模式生物Drosophila melanogaster来确定神经元通路，通过这些通路，时钟细胞建立摄食行为的昼夜节律，并进一步描绘摄食节律如何与外周代谢节律协调。这些实验将与实验室的博士后和本科生研究人员合作进行，他们也将担任暑期高中实习计划的导师，该计划将扩大参与传统上在科学领域代表性不足的群体。要了解昼夜节律系统调节行为输出并将其与生理节律协调的方式，需要分析新的昼夜节律终点，休息和活动，这是迄今为止大多数昼夜节律研究的焦点。目的1将使用一种新开发的摄食监测器来确定中枢时钟调节摄食节律的细胞逻辑。为了确定不同的中央时钟机制是否控制进食和运动活动节律，将在改变离散时钟细胞群中的分子时钟功能或神经元活动的遗传操作之后测量进食节律的周期和强度。目标2将研究下游输出通路，通过这些通路产生摄食节律。为了制定行为节律，昼夜节律信息必须通过输出通路传输到调节行为的大脑区域。Cavanaugh实验室最近暗示SIFa肽表达神经元是控制进食的昼夜输出途径的组成部分。为了继续追踪昼夜摄食回路，将进行基于RNA干扰的行为筛选，以鉴定其中必须存在SIFa受体以实现正常摄食节律的细胞。最后，目标3将研究进食和代谢节律是如何通过时钟网络协调的。脂肪体是一个外周时钟组织，提供代谢功能。将采用转录组学和代谢组学相结合的方法来确定大脑或脂肪体中SIFa信号传导或选择性分子钟废除的损失如何影响脂肪体基因振荡和整个动物代谢物丰度。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Inducible Reporter Lines for Tissue-specific Monitoring of Drosophila Circadian Clock Transcriptional Activity

用于果蝇昼夜节律时钟转录活动组织特异性监测的诱导报告基因系

• DOI: 10.1177/07487304221138946
• 发表时间: 2022
• 期刊: Journal of Biological Rhythms
• 影响因子: 3.5
• 作者: Mather, Lilyan M.;Cholak, Meghan E.;Morfoot, Connor M.;Curro, Katherine C.;Love, Jacob;Cavanaugh, Daniel J.
• 通讯作者: Cavanaugh, Daniel J.