Non-transcriptional regulation of circadian physiology
昼夜节律生理学的非转录调节
基本信息
- 批准号:10223290
- 负责人:
- 金额:$ 37.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-11 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Circadian clocks are endogenous protein machines that integrate external time cues and
internal metabolic states to regulate daily rhythms in physiology and behavior in organisms from
all kingdoms of life. In the natural world, environmental zeitgebers enable the animal circadian
clock to control timing of food intake. Nutrient influx can therefore provide metabolic signals to
reinforce environmental signals, promoting synchrony in circadian physiology to balance
metabolism and energy use. Initial efforts to dissect the underpinnings of the circadian oscillator
and its control over rhythms of life focused on regulation at the transcriptional level, as the core
oscillator proteins are transcription factors that collaborate to govern rhythmic expression of genes
involved in diverse cellular processes. More recent studies have uncovered complementary non-transcriptional mechanisms, including protein post-translational modifications (PTMs), that are
critical for circadian timekeeping. The overall goal of this project is to understand the
mechanisms by which metabolic and environmental signals integrate at the post-translational
level to regulate circadian physiology, and more importantly the consequences when these
signals that have evolved to cooperate are in conflict. We will use the diurnal Drosophila model
to test the central hypothesis that nutrient influx through clock-controlled feeding activity
regulates the interplay between phosphorylation and O-linked N-Acetylglucosaminylation (O-GlcNAcylation) of cellular proteins to modulate time-of-day specific functions. Protein O-GlcNAcylation is highly sensitive to metabolic input and may play a dominant role in extensive
remodeling of cellular protein functions, bypassing changes in gene expression. In Aim 1, we will
use time-restricted feeding (TRF) in combination with targeted metabolomics and
chemoenzymatic O-GlcNAc labeling to establish the relationships between feeding-fasting cycle,
nutrient influx, and O-GlcNAcylation status of cellular proteins. In Aim 2, we will identify cellular
proteins that exhibit daily interplay between O-GlcNAcylation and phosphorylation using label-free proteomic approaches. In Aim 3, we will characterize the function of clock protein O-GlcNAcylation events by utilizing tried-and-true molecular and Drosophila behavioral assays. By addressing the 3 questions: When, What, and Why, we will advance our understanding on
metabolic regulation of circadian physiology via post-translational mechanisms. This project will
have broad significance as cross-talk between protein phosphorylation and O-GlcNAcylation is
extensive and modulates a wide range of cellular processes. Our findings may identify new
therapeutic targets to alleviate circadian and metabolic disorders.
昼夜节律是内源性蛋白质机器,可以整合外部时间提示和
内部代谢状态以调节生物体生理和行为的每日节奏
生活的所有王国。在自然世界中,环境时机使动物昼夜节律启用
控制食物摄入时间的时钟。因此,营养流入可以提供代谢信号
加强环境信号,促进昼夜节律生理学的同步以平衡
代谢和能源使用。剖析昼夜节振荡器的基础的最初努力
它对生命节奏的控制集中在转录级别的调节上,作为核心
振荡蛋白是转录因子,可协作控制基因的节奏表达
参与各种细胞过程。最近的研究发现了互补的非转录机制,包括蛋白质后翻译后修饰(PTMS),即
对于昼夜节时间至关重要。该项目的总体目标是了解
代谢和环境信号在翻译后整合的机制
调节昼夜节律生理学的水平,更重要的是后果
发展为合作的信号正在发生冲突。我们将使用昼夜果蝇模型
为了测试中心假设,即通过时钟控制的喂养活动营养涌入
调节细胞蛋白的磷酸化和O连接的N-乙酰葡萄糖氨基化(O-Glcnacylation)之间的相互作用,以调节日期特定功能。蛋白O-Glcnacylation对代谢输入高度敏感,并且可能在广泛的
细胞蛋白功能的重塑,绕过基因表达的变化。在AIM 1中,我们将
使用时间限制的喂养(TRF)与靶向代谢组和
化学酶O-GlCNAC标记以建立喂食周期之间的关系,
养分流入和细胞蛋白的O-Glcnacylation状态。在AIM 2中,我们将确定蜂窝
使用无标签蛋白质组学方法在O-Glcnacylation和磷酸化之间表现出每日相互作用的蛋白质。在AIM 3中,我们将通过利用久经考验的分子和果蝇行为分析来表征时钟蛋白O-Glcnacylation事件的功能。通过解决3个问题:何时,什么以及为什么,我们将提高我们的理解
通过翻译后机制对昼夜节律生理的代谢调节。这个项目将
由于蛋白质磷酸化和O-Glcnacylation之间的串扰是
广泛并调节广泛的细胞过程。我们的发现可能确定了新的
减轻昼夜节律和代谢障碍的治疗靶标。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据
数据更新时间:2024-06-01
JOANNA Chungyen CH...的其他基金
Non-transcriptional regulation of circadian physiology
昼夜节律生理学的非转录调节
- 批准号:1040610910406109
- 财政年份:2021
- 资助金额:$ 37.89万$ 37.89万
- 项目类别:
Non-transcriptional regulation of circadian physiology
昼夜节律生理学的非转录调节
- 批准号:1001721110017211
- 财政年份:2019
- 资助金额:$ 37.89万$ 37.89万
- 项目类别:
Non-transcriptional regulation of circadian physiology
昼夜节律生理学的非转录调节
- 批准号:1066943210669432
- 财政年份:2019
- 资助金额:$ 37.89万$ 37.89万
- 项目类别:
Non-transcriptional regulation of circadian physiology
昼夜节律生理学的非转录调节
- 批准号:1046175610461756
- 财政年份:2019
- 资助金额:$ 37.89万$ 37.89万
- 项目类别:
Non-transcriptional regulation of circadian physiology
昼夜节律生理学的非转录调节
- 批准号:1083532810835328
- 财政年份:2019
- 资助金额:$ 37.89万$ 37.89万
- 项目类别:
Postbaccalaureate Research Education Program at UC Davis
加州大学戴维斯分校学士后研究教育项目
- 批准号:1055968810559688
- 财政年份:2017
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The role of DBT and NEMO-dependent phosphoproteome in regulating animal clockwork
DBT 和 NEMO 依赖性磷酸蛋白质组在调节动物时钟中的作用
- 批准号:85033938503393
- 财政年份:2013
- 资助金额:$ 37.89万$ 37.89万
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The role of DBT and NEMO-dependent phosphoproteome in regulating animal clockwork
DBT 和 NEMO 依赖性磷酸蛋白质组在调节动物时钟中的作用
- 批准号:87344408734440
- 财政年份:2013
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- 项目类别:
The role of DBT and NEMO-dependent phosphoproteome in regulating animal clockwork
DBT 和 NEMO 依赖性磷酸蛋白质组在调节动物时钟中的作用
- 批准号:93382529338252
- 财政年份:2013
- 资助金额:$ 37.89万$ 37.89万
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The role of DBT and NEMO-dependent phosphoproteome in regulating animal clockwork
DBT 和 NEMO 依赖性磷酸蛋白质组在调节动物时钟中的作用
- 批准号:91328149132814
- 财政年份:2013
- 资助金额:$ 37.89万$ 37.89万
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