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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：
10835328
负责人：
JOANNA Chungyen CHIU
金额：
$ 13.7万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10835328
关键词：
Animal Model Animals Behavior Behavioral Biochemical Biological Assay Biological Rhythm Biology Biotin Brain Bypass Cell physiology Cells Chronic Disease Circadian Dysregulation Circadian Rhythms Collaborations Cues Cysteine Diet Drosophila genus Eating Elements Environment Equilibrium Exhibits Fasting Future Gene Expression Genetic Genetic Transcription Goals High Fat Diet Homeostasis Hour Human Immune System Diseases Knowledge Life Style Light Link Lipids Liver Maintenance Malignant Neoplasms Mass Spectrum Analysis Mediating Membrane Metabolic Metabolic Diseases Metabolism Modeling Modernization Modification Molecular Molecular Biology Mus Nutrient Nutritional Organ Output Palmitates Pathology Periodicity Peripheral Phase Phosphorylation Physiological Physiology Play Post-Translational Protein Processing Process Protein S Proteins Proteome Proteomics Publishing Regulation Regulatory Pathway Reporting Role Saturated Fatty Acids Schedule Signal Transduction Site Sleep Wake Cycle Stress Technology Temperature Testing Time Time-restricted feeding Tissues Western Blotting Work blood-brain barrier permeabilization circadian circadian pacemaker circadian regulation circadian transcriptome feeding fly healthspan human disease insight lipid metabolism lipidomics model organism mouse model nervous system disorder new therapeutic target nutrition palmitoylation programs protein function protein protein interaction receptor response sugar transcription factor

项目摘要

PROJECT SUMMARY Robust daily biological rhythms are key hallmarks of animal healthspan and are strongly regulated by circadian clocks. These cell-autonomous molecular timers enable animals to adapt to predictable daily changes in their environment. Clock-controlled outputs are all-encompassing and clock disruption is associated with a wide range of pathologies and chronic diseases. In the natural world, environmental signals, e.g. light and temperature, enable animal circadian clocks to control timing of food intake. Nutrient influx can therefore provide metabolic signals to reinforce environmental signals, promoting synchrony in cellular physiology to balance metabolism and energy use. Efforts to understand the underpinnings of circadian clocks and their control over daily biological rhythms have long focused on regulation at the transcriptional level, as 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 robust daily rhythms. The overall goal of this project is to advance our understanding of the role of nutrient-dependent PTMs in mediating metabolic regulation of time-of-day-specific protein functions to orchestrate daily biological rhythms. We will use the diurnal Drosophila model to test the central hypothesis that metabolic signals from clock-controlled feeding activity and cellular metabolism regulate rhythmic S-palmitoylation of cellular proteins, and S-palmitoylation is necessary for maintenance of robust daily biological rhythms. S-palmitoylation is the only reversible lipid PTM; it is the attachment of palmitate, a saturated fatty acid, to cysteines. S- palmitoylation targets a wide range of proteins from transcription factors to membrane receptors, and is known to alter their stability, activity, localization, and protein-protein interactions. The specific aims of this project are to investigate the mechanisms by which clock-dependent metabolic signals regulate S-palmitoylation rhythms and how these rhythms are impacted by nutritional stress (Aim 1); to identify proteins that exhibit daily rhythms in S-palmitoylation (Aim 2); and to determine if palmitoylation regulates daily biology rhythms (Aim 3). This project will advance our long-term goal to integrate post-translational regulatory pathways and obtain a comprehensive understanding of how daily biological rhythms are regulated by diet, nutrition, and timing of metabolic input. This project will have broad significance as misregulation in S- palmitoylation has been linked to a plethora of human diseases including cancer, metabolic, neurological, and immunological disorders.

项目总结