Regulation of macrophage metabolism in aged muscle during recovery
衰老肌肉恢复过程中巨噬细胞代谢的调节
基本信息
- 批准号:10460028
- 负责人:
- 金额:$ 62.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-15 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:AdoptedAgingAnti-Inflammatory AgentsAttenuatedAutomobile DrivingBone MarrowBone Marrow Cell TransplantationBone Marrow CellsBone Marrow TransplantationCell physiologyCellsCharacteristicsChemicalsCitric Acid CycleCoupledDataDefectDevelopmentDisuse AtrophyElderlyEnzymesEventExhibitsFibrosisFunctional disorderFutureGeneticGenetic TranscriptionGlycolysisGrowth FactorHealthHematopoieticHindlimb SuspensionHumanImmobilizationImmune systemImpairmentIn VitroIndividualInflammationInflammatoryInflammatory ResponseInterleukin-1 betaInterruptionKnowledgeLeadLimb structureLiteratureMacrophage ActivationMediatingMetabolicMetabolic DiseasesMetabolismMethodologyMusMuscleMuscle functionMuscle satellite cellOperative Surgical ProceduresOxidative PhosphorylationPhenotypeRecoveryRecovery SupportRegulationResolutionRodentRoleSerumSkeletal MuscleStimulusSuccinatesSuggestionTestingTherapeuticTranscriptTranslatingage relatedagedbone agingcytokinedisabilityexperimental studyextracellularfall riskfallshypoxia inducible factor 1in vivomacrophagemitochondrial dysfunctionmouse geneticsmouse modelmuscle agingmuscle regenerationnovelpre-clinicalprecursor cellpreventprogramsreduced muscle massresponserestorationsarcopeniasingle-cell RNA sequencingstemstem cell functiontherapeutic developmenttranscription factortranscriptomeyoung adult
项目摘要
Abstract
Muscle regrowth and function following disuse atrophy in aged muscle is significantly compromised, and this
increases the risk for falls, long-term disability and loss of independence. Therapeutic strategies to enhance
muscle recovery are non-existent stemming from a poor understanding of cellular mechanism during regrowth
in aging muscle. Invasion of muscle macrophages and polarization to pro- and anti-inflammatory states are
critical to promote muscle stem cell function and the full resolution of muscle and function following disuse. More
recently, macrophage metabolism has been shown to be tightly coupled to the inflammatory state of activated
macrophages and regulated by transcription factors such as HIF-1α and accumulation of TCA intermediates
such as succinate. Our preliminary data in impaired aged muscle during early recovery supports decreased
macrophage succinate and HIF-1α corresponding to a reduced macrophage glycolytic and inflammatory
program and functional characteristics. Therefore, using novel mouse genetic and bone marrow transfer
experiments, along with chemical approaches and in vitro studies, we will test if succinate and HIF-1α are key
regulatory steps for macrophage metabolic and inflammatory activation during regrowth from disuse in aging
muscle and if this dysfunction arises from an aged immune system. In Aim 2, we will translate our pre-clinical
findings to young and older humans and confirm our hypothesis by extensively characterizing muscle
macrophage metabolic and inflammatory functional states in vivo and in vitro during recovery from disuse
atrophy. We anticipate that the findings will identify macrophage metabolism as a future target to accelerate the
recovery of aged muscle following disuse related events (e.g., surgery, illness).
摘要
在老年肌肉中废用性萎缩后的肌肉再生和功能显著受损,并且这
增加了福尔斯跌倒、长期残疾和丧失独立性的风险。治疗策略,以提高
由于对再生过程中的细胞机制了解不足,肌肉恢复不存在
老化的肌肉。肌肉巨噬细胞的入侵以及向促炎和抗炎状态的极化是
关键是促进肌肉干细胞功能和废用后肌肉和功能的完全解决。更
最近,巨噬细胞代谢已被证明与活化的巨噬细胞的炎症状态紧密相关,
巨噬细胞和调节转录因子,如HIF-1α和积累TCA中间体
如琥珀酸盐。我们的初步数据,在受损的老年肌肉在早期恢复支持减少
巨噬细胞琥珀酸和HIF-1α对应于减少的巨噬细胞糖酵解和炎症
程序和功能特性。因此,使用新的小鼠遗传和骨髓移植,
沿着化学方法和体外研究,我们将测试琥珀酸和HIF-1α是否是关键
衰老废用再生过程中巨噬细胞代谢和炎症活化的调节步骤
肌肉,如果这种功能障碍是由老化的免疫系统引起的。在目标2中,我们将把临床前
研究结果对年轻人和老年人,并证实了我们的假设,通过广泛表征肌肉
废用恢复期间体内和体外巨噬细胞代谢和炎症功能状态
萎缩我们预计,这些发现将确定巨噬细胞代谢作为未来的目标,以加速
在废用相关事件后老化肌肉的恢复(例如,手术、疾病)。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Micah J Drummond其他文献
Micah J Drummond的其他文献
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{{ truncateString('Micah J Drummond', 18)}}的其他基金
MicroRNA regulation of chronic inflammation during aging
MicroRNA对衰老过程中慢性炎症的调节
- 批准号:
10817445 - 财政年份:2022
- 资助金额:
$ 62.69万 - 项目类别:
Regulation of macrophage metabolism in aged muscle during recovery
衰老肌肉恢复过程中巨噬细胞代谢的调节
- 批准号:
10622569 - 财政年份:2022
- 资助金额:
$ 62.69万 - 项目类别:
MicroRNA regulation of chronic inflammation during aging
MicroRNA对衰老过程中慢性炎症的调节
- 批准号:
10531053 - 财政年份:2022
- 资助金额:
$ 62.69万 - 项目类别:
Targeting macrophage polarization to optimize muscle regrowth from disuse atrophy
靶向巨噬细胞极化以优化废用性萎缩的肌肉再生
- 批准号:
10228828 - 财政年份:2020
- 资助金额:
$ 62.69万 - 项目类别:
Role of immune cells on the growth and recovery of aging muscle
免疫细胞对衰老肌肉生长和恢复的作用
- 批准号:
10197500 - 财政年份:2019
- 资助金额:
$ 62.69万 - 项目类别:
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