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:
- 金额:$ 45.38万
- 依托单位:
- 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:
- 关键词:ARNTL geneAblationAgingAtrophicAttenuatedAutomobile DrivingAutophagocytosisCellsChIP-seqCircadian DysregulationCircadian desynchronyCoupledDefectEtiologyFRAP1 geneFunctional disorderGeneticGenetic ModelsGenetic TranscriptionGlucoseGoalsGrowthHomeostasisImpairmentInsulinInsulin ResistanceInterventionKnowledgeLabelLife StyleLinkLipidsMaintenanceMediatingMetabolicMetabolic PathwayMetabolismModelingModernizationMolecularMuscleMuscle DevelopmentMuscle FibersMuscle ProteinsMuscular AtrophyNutrientObesityOutcomeOutputPIK3CG genePathway interactionsPeriodicityPhysiologicalPlayPrevalenceProtein BiosynthesisProteinsProteomicsRegulationResearchResearch SupportResistanceRoleSignal TransductionSkeletal MuscleStimulusTestingTherapeuticTimeTranscription CoactivatorTranscriptional RegulationTranslationsWasting Syndromecircadiancircadian pacemakercircadian regulationfeedinggain of functiongenetic testingglucose metabolismimprovedinsulin sensitivitylipid metabolismloss of functionmTOR Signaling Pathwaymetabolomicsmouse modelmultiple omicsmuscle formnobiletinnovelnutrient metabolismpharmacologicpreventprotein degradationprotein metabolismproteostasisresponsesarcopeniasarcopenic obesitysensorshift worktranscriptomics
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.
项目摘要
生物钟赋予代谢途径时间控制,其中断导致胰岛素抵抗
和肥胖。骨骼肌在营养代谢和蛋白质稳态中起着关键作用。我们和其他人
证明了肌肉内在时钟调节骨骼肌的发育、生长和代谢。
尽管对葡萄糖和脂质代谢的昼夜节律调节进行了广泛的研究,但目前仍存在一种
关于决定肌肉质量的蛋白质代谢中的时钟功能的知识差距。此外,本发明还提供了一种方法,
尽管昼夜节律失调在现代生活方式中普遍存在,但潜在的昼夜节律病因学
肌肉萎缩和代谢能力受损仍然是未知的。我们发现了一种新颖的时钟驱动的
骨骼肌中PI 3 K-Akt-mTORC 1信号传导的时间控制不依赖于进食诱导
activation.令人惊讶的是,模仿轮班工作的生物钟中断导致了进行性肌肉萎缩
伴随着受损的PI 3 K-Akt信号传导和升高的蛋白质周转。此外,机械研究
揭示了胰岛素/Igf-1-PI 3 K-Akt-mTOR信号级联的生物钟转录控制。这些
研究结果,以及先前的研究支持一个假设,即肌肉内在的时钟赋予时间
控制PI 3 K-Akt-mTOR级联以驱动蛋白质代谢和胰岛素敏感性,并且该机制
是昼夜节律紊乱引起的肌肉萎缩和胰岛素抵抗的基础。这个项目的首要目标是
全面定义肌肉营养中新发现的时钟-PI 3 K-Akt-mTOR调节轴
体内平衡和肌肉质量调节。具体而言,我们将利用我们独特的时钟调制模型,
多组学方法,以全面定义的分子机制负责和
时钟-Akt-mTOR调节轴在蛋白质代谢、胰岛素敏感性和
肌肉质量维持。更重要的是,我们建议测试遗传和药理学时钟增强
干预措施,以抵消肌肉合成代谢和代谢缺陷引起的时钟中断。的结果
该建议可以揭示肌少症中代谢能力受损的生理节律病因学,
生物钟靶向干预的机制基础。
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)
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{{ truncateString('Ke Ma', 18)}}的其他基金
Circadian clock regulation of metabolic pathways in aging
衰老过程中代谢途径的昼夜节律时钟调节
- 批准号:
10901023 - 财政年份:2023
- 资助金额:
$ 45.38万 - 项目类别:
Circadian Clock Control of Adipose Depot Development and Function
脂肪库发育和功能的昼夜节律时钟控制
- 批准号:
10062969 - 财政年份:2017
- 资助金额:
$ 45.38万 - 项目类别:
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