权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Circadian clock and temporal control in nutrient metabolism

昼夜节律时钟和营养代谢的时间控制

基本信息

批准号：
10754101
负责人：
Ke Ma
金额：
$ 45.38万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10754101
关键词：
ARNTL gene Ablation Aging Atrophic Attenuated Automobile Driving Autophagocytosis Cells ChIP-seq Circadian Dysregulation Circadian desynchrony Coupled Defect Etiology FRAP1 gene Functional disorder Genetic Genetic Models Genetic Transcription Glucose Goals Growth Homeostasis Impairment Insulin Insulin Resistance Intervention Knowledge Label Life Style Link Lipids Maintenance Mediating Metabolic Metabolic Pathway Metabolism Modeling Modernization Molecular Muscle Muscle Development Muscle Fibers Muscle Proteins Muscular Atrophy Nutrient Obesity Outcome Output PIK3CG gene Pathway interactions Periodicity Physiological Play Prevalence Protein Biosynthesis Proteins Proteomics Regulation Research Research Support Resistance Role Signal Transduction Skeletal Muscle Stimulus Testing Therapeutic Time Transcription Coactivator Transcriptional Regulation Translations Wasting Syndrome circadian circadian pacemaker circadian regulation feeding gain of function genetic testing glucose metabolism improved insulin sensitivity lipid metabolism loss of function mTOR Signaling Pathway metabolomics mouse model multiple omics muscle form nobiletin novel nutrient metabolism pharmacologic prevent protein degradation protein metabolism proteostasis response sarcopenia sarcopenic obesity sensor shift work transcriptomics

项目摘要

Project Summary The circadian clock confers temporal control to metabolic pathways, and its disruption leads to insulin resistance and obesity. Skeletal muscle plays a critical role in nutrient metabolism and protein homeostasis. We and others demonstrated that the muscle-intrinsic clock regulates skeletal muscle development, growth, and metabolism. Despite the extensive studies of circadian regulation in glucose and lipid metabolism, there is a current knowledge gap regarding clock function in protein metabolism that determines muscle mass. In addition, although circadian misalignment is prevalent in a modern lifestyle, potential circadian etiologies underlying muscle wasting and impaired metabolic capacity remains unknown. We have identified a novel clock-driven temporal control of PI3K-Akt-mTORC1 signaling in skeletal muscle that is independent of feeding-induced activation. Surprisingly, clock disruption mimicking shiftwork resulted in progressive muscle atrophy accompanied with impaired PI3K-Akt signaling and elevated protein turnover. Furthermore, mechanistic studies revealed circadian clock transcriptional control of the Insulin/Igf-1-PI3K-Akt-mTOR signaling cascade. These findings, together with prior research support a hypothesis that that the muscle-intrinsic clock confers temporal control in PI3K-Akt-mTOR cascade to drive protein metabolism and insulin sensitivity, and this mechanism underlies circadian disruption-induced muscle atrophy and insulin resistance. The overarching goal of this project is to comprehensively define this newly discovered clock-PI3K-Akt-mTOR regulatory axis in muscle nutrient homeostasis and muscle mass regulation. Specifically, we will leverage our unique clock modulation models with multi-omics approaches to comprehensively define the molecular mechanisms responsible for and the physiological significance of the clock-Akt-mTOR regulatory axis in protein metabolism, insulin sensitivity and muscle mass maintenance. More importantly, we propose to test genetic and pharmacological clock-augmenting interventions to counteract muscle anabolic and metabolic deficits induced by clock disruption. The outcome of this proposal may uncover a circadian etiology underlying impaired metabolic capacity in sarcopenia and provide the mechanistic basis for clock-targeting interventions.

项目总结