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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：
10017211
负责人：
JOANNA Chungyen CHIU
金额：
$ 38.01万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
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：
https://reporter.nih.gov/project-details/10017211
关键词：
ARNTL gene Address Animal Model Animals Automobile Driving Behavior Behavioral Behavioral Assay Biochemical Biological Assay Bypass Cell physiology Clock protein Conflict (Psychology)Cues Drosophila genus Eating Elements Enzymes Equilibrium Event Exhibits Fasting Gene Expression Genetic Transcription Goals Hexosamines Human Investigation Label Life Life Style Light Link Liver Mass Fragmentography Measurement Measures Metabolic Metabolic Diseases Metabolism Modeling Modernization Molecular Mus Mutation Nutrient Organism Pathway interactions Periodicity Phase Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Phosphotransferases Physiological Physiology Play Post-Translational Protein Processing Proteins Proteomics Publishing Regulation Role Schedule Series Serine Signal Transduction Site Speed Testing Threonine Time Time-restricted feeding Transcription Repressor Transgenic Organisms Work cellular targeting circadian circadian pacemaker circadian regulation daily functioning feeding fly glycoproteomics metabolomics new therapeutic target programs protein function response time use tissue culture transcription factor transcriptome

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.

生物钟是内源性蛋白质机器，整合了外部时间线索和