Mechanisms of GM-CSF-mediated metabolic regulation of monocyte function for control of pulmonary infection
Mechanisms of GM-CSF-mediated metabolic regulation of monocyte function for control of pulmonary infection
批准号:
10462692
负责人:
Xin Liu
金额:
$9.46万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-08-05 至 2023-07-31
关键词:
ATP Citrate (pro-S)-LyaseAcetatesAcetyl Coenzyme AAddressAnimal ModelAnti-Bacterial AgentsAntibiotic TherapyBacteriaBacterial InfectionsBacterial PneumoniaCause of DeathCell Differentiation processCell physiologyCellsCommunitiesComplementDataDendritic CellsDevelopmentEnzymesEpigenetic ProcessExhibitsFibrinogenGlycolysisGoalsGranulocyte-Macrophage Colony-Stimulating FactorHistone AcetylationHomeostasisHost DefenseITGAM geneImmunocompromised HostImmunologicsImmunotherapyInfectionInfection ControlInflammatoryKnockout MiceKnowledgeLegionella pneumophilaLegionnaires&apos DiseaseLung infectionsMaintenanceMediatingMetabolicMetabolic ControlMetabolismMitochondriaMusMyeloid CellsNosocomial pneumoniaPersonsPlayPneumoniaProductionPulmonary InflammationRegulationResolutionRespirationRoleSignal TransductionSourceSpecificityTestingTissuesaerobic glycolysisbaseblood glucose regulationconditional knockoutcytokinecytokine therapyenhancing factorglucose metabolismhistone acetyltransferasein vivoinsightlactate dehydrogenase Aloss of functionlung pathogenmonocytemortalitypneumonia treatmentreconstitutionresponserestorationtargeted treatment
中文摘要
肺炎仍然是世界范围内导致死亡的主要传染病。Ly6chi单核细胞(IMCs)有一种基本的
在维持体内平衡和控制肺部感染方面的作用。虽然它现在已经被公认为
IMCs的功能受微环境控制,局部细胞因子环境对IMC功能的影响
仍然难以捉摸。粒细胞-巨噬细胞集落刺激因子(GM-CSF),最重要的宿主之一
调节iMCs功能的细胞因子在宿主防御几种显著的
然而,GM-CSF调节IMC功能的确切机制
肺部感染仍未完全了解。我最近的研究发现GM-CSF促进
IMCs和MC来源的细胞产生炎性细胞因子控制嗜肺乳杆菌感染
GM-CSF促进系膜细胞有氧糖酵解,这是依赖GM-CSF的炎性细胞因子所必需的
体外生产。这项提议的目标是解决关于
GM-CSF介导IMC功能代谢调控肺功能的机制
体内感染。在我的初步研究中,我观察到对iMCs有氧糖酵解的抑制表现出
体内感染嗜肺乳杆菌时炎性细胞因子的产生显著减少,并且
组蛋白乙酰转移酶的抑制作用--组蛋白乙酰辅酶A代谢下游的关键酶
乙酰化,体外取消GM-CSF依赖的炎性细胞因子的产生。这些初步调查结果
提出GM-CSF支持IMC功能以控制肺部感染的中心假说
有氧糖酵解介导的表观遗传重编程。我的中心假设将由3个目标来检验:目标1
将检验GM-CSF支持IMC功能活动以控制嗜肺乳杆菌感染的假设。目标
2将验证GM-CSF调节iMCs有氧糖酵解的假设,这是MC介导的必需的。
抗菌功能。目标3将验证有氧糖酵解支持乙酰辅酶A介导组蛋白的假设
乙酰化,有助于GM-CSF对MC功能的调节。总体而言,这项建议将提供
GM-CSF介导的IMC抗菌代谢调控机制的研究
肺炎。
英文摘要
Pneumonia remains the leading infectious cause of death worldwide. Ly6Chi monocytes (iMCs) have an essential
role in the maintenance of homeostasis and control of pulmonary infection. While it has now been recognized
that the functions of iMCs are governed by microenvironment, the impact of local cytokine milieu on iMC function
remains elusive. Granulocyte-macrophage colony-stimulating factor (GM-CSF), one of the most important host
cytokines that modulate the functions of iMCs, plays a critical role in host defense against several significant
pulmonary pathogens; however, the precise mechanisms by which GM-CSF regulates iMC function to control
pulmonary infection is still not fully understood. My recent studies have discovered that GM-CSF promotes
inflammatory cytokine production by iMCs and MC-derived cells for control of L. pneumophila infection, and that
GM-CSF enhances aerobic glycolysis of MCs which is required for GM-CSF-dependent inflammatory cytokine
production ex vivo. The goal of this proposal is to address the critical gap in knowledge regarding the
mechanisms underlying GM-CSF-mediated metabolic regulation of iMC function for control of pulmonary
infection in vivo. In my preliminary studies, I observed that inhibition of aerobic glycolysis in iMCs exhibited a
significant reduction of inflammatory cytokine production during in vivo L. pneumophila infection, and that
inhibition of histone acetyltransferase, a key enzyme downstream of Acetyl-CoA metabolism for histone
acetylation, abolished GM-CSF-dependent inflammatory cytokine production ex vivo. These preliminary findings
provoke the central hypothesis that GM-CSF supports iMC function for control of pulmonary infection through
aerobic glycolysis-mediated epigenetic reprogramming. My central hypothesis will be tested by 3 aims: Aim 1
will test the hypothesis that GM-CSF supports iMC functional activities to control L. pneumophila infection. Aim
2 will test the hypothesis that GM-CSF regulates aerobic glycolysis of iMCs, which is required for MC-mediated
antibacterial function. Aim 3 will test the hypothesis that aerobic glycolysis supports acetyl-CoA-mediated histone
acetylation, which contributes to GM-CSF regulation of MC function. Overall, this proposal will provide insight
into the mechanisms underlying GM-CSF-mediated metabolic control of iMC function against bacterial
pneumonia.
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会议论文
Mechanisms of GM-CSF-mediated metabolic regulation of monocyte function for control of pulmonary infection
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批准号:10877377
-
项目类别:
-
资助金额:$24.9万
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财政年份:2023
-
负责人:Xin Liu
-
依托单位:
Mechanisms of GM-CSF-mediated metabolic regulation of monocyte function for control of pulmonary infection
-
批准号:10302014
-
项目类别:
-
资助金额:$9.46万
-
财政年份:2021
-
负责人:Xin Liu
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依托单位:
Molecular Basis of Gene Regulation by Polycomb Repressive Complex 2
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批准号:10373974
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项目类别:
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资助金额:$61.15万
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财政年份:2020
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负责人:Xin Liu
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依托单位:
Molecular Basis of Gene Regulation by Polycomb Repressive Complex 2
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批准号:10590674
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项目类别:
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资助金额:$61.15万
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财政年份:2020
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负责人:Xin Liu
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依托单位:
Molecular Basis of Gene Regulation by Polycomb Repressive Complex 2
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批准号:10581251
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资助金额:$11.55万
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财政年份:2020
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负责人:Xin Liu
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依托单位:
Structural Basis of Gene Regulation by Polycomb Repressive Complex 2
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批准号:9219491
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依托单位:
Molecular Mechanisms of Promoter-Terminator Gene Looping
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批准号:8865248
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项目类别:
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资助金额:$30.53万
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财政年份:2015
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负责人:Xin Liu
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依托单位:
Parent-of-Origin Effects on Food Allergy
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批准号:8488814
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项目类别:
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资助金额:$7.35万
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财政年份:2013
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负责人:Xin Liu
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依托单位:
Vitamin D and Food Allergy: a Prospective Birth Cohort Study
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批准号:7874959
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资助金额:$18.38万
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负责人:Xin Liu
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依托单位:
Vitamin D and Food Allergy: a Prospective Birth Cohort Study
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批准号:8044712
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资助金额:$21.83万
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依托单位:
Sleep and Adiposity: A Prospective Twin Study
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批准号:7672283
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资助金额:$50.38万
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财政年份:2006
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负责人:Xin Liu
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依托单位:
海外基金