CREB Instruction of Macrophage Fate and Lung fluid homeostasis
CREB对巨噬细胞命运和肺液稳态的指导
基本信息
- 批准号:10625859
- 负责人:
- 金额:$ 15.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-20 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAcetyl Coenzyme AAcute Lung InjuryAcute Respiratory Distress SyndromeAlveolarAlveolar MacrophagesBACH2 geneBindingBiological AssayCell NucleusChIP-seqChromatinCritical IllnessCyclic AMPCyclic AMP Response ElementCyclic AMP-Responsive DNA-Binding ProteinDataDevelopmentDiseaseEndotheliumEpigenetic ProcessEpitheliumExhibitsExtravasationFluid BalanceGene ExpressionGenerationsGenesGeneticGenetic TranscriptionHistone AcetylationHomeostasisITGAM geneITGAX geneImmuneImpairmentInflammatoryInflammatory ResponseInjuryInstructionLeukocytesLifeLungLung CapacityMacrophageMitochondriaMusMyeloid CellsNuclearPathway interactionsPatientsPlasmaPopulationProductionPseudomonas aeruginosa infectionPyruvate Dehydrogenase ComplexRecoveryRegulationRegulatory ElementResearchRoleSentinelSignal InductionSignal PathwaySortingSourceTestingTherapeuticTissuesTransposaseVascular Permeabilitiescell typechromatin remodelingcytokinehistone modificationinjury and repairinsightinterstitiallung injurylung repairlung vascular injurymonocytemortalitymultiple omicsnovelnovel therapeutic interventionpharmacologicpreventprogramspromoterprotein expressionpyruvate dehydrogenase kinase 4repair strategyrestorationsingle-cell RNA sequencingtissue injurytissue repairtranscription factortranscriptome sequencingvascular injury
项目摘要
Abstract
Recovery from severe forms of inflammatory vascular injury, such as acute lung injury (ALI), depends on the
lung's capacity to rapidly activate tissue repair pathways. Macrophages (Mφ), the most abundant sentinel
immune cell type in the lung, are required for restoration of tissue-fluid homeostasis following injury, but the
identity of the reparative Mφ subpopulations and how they are generated remain elusive. Here, we have
discovered a subset of the alveolar Mφ (AMφ) population that is required to maintain lung fluid homeostasis
basally and induce tissue repair after injury. Our Supporting Data show that: 1) loss of cAMP Response
Element Binding (CREB) protein expression in myeloid cells (Creb∆LyzM mice) arrest a subpopulation of the AMφ
lineage at the pre-AMφ stage, leading to decreased AMφ generation and increased lung vascular permeability
basally; 2) Creb∆LyzM mice failed to resolve injury post-LPS challenge and died more rapidly after Pseudomonas
aeruginosa infection; 3) transcriptome sequencing (RNAseq) and chromatin accessibility profiling (ATACseq) of
flow-sorted CREB-null AMφ have markedly altered gene expression and chromatin remodeling; and 4) CREB is
required to inhibit excessive production of nuclear acetyl-CoA from the pyruvate dehydrogenase complex (PDC)
through synthesis of pyruvate dehydrogenase kinase 4 (PDK4). Based on these provocative Preliminary Data,
in Aim#1, we will test the hypothesis that CREB transcriptionally promotes differentiation of this barrier
reparative AMφ subpopulation. In Aim#2, we will investigate that CREB regulates reparative AMφ generation
by controlling epigenetic modifications of histones thereby leading to AMφ gene transcription. Here, we will
address the novel concept that the transcriptional activity of CREB is required to upregulate PDK4 expression,
which in turn prevents transport of its target, PDC, from mitochondria to the nucleus thereby suppressing
excessive nuclear acetyl Co-A generation and limiting epigenetic modifications of histones, leading to gene
transcription that induces the barrier reparative AMφ population. These studies will employ a rigorous multi-
omics approach (single-cell RNA-, ATAC-and Chip-sequencing) and functional assays in genetically altered mice
including Rosa-CrebCxcxr3-ERT mice (in which CREB is conditionally deleted in monocytes/interstitial macrophages)
to define the role of CREB transcriptional activity in generating the reparative AMφ population. Understanding
how this barrier reparative AMɸ subset is generated should make it possible to enhance differentiation of this
subset during injury by pharmacological or genetic means, thereby reducing the mortality of ALI and related
conditions.
摘要
从严重形式的炎性血管损伤(如急性肺损伤(ALI))中恢复取决于
肺快速激活组织修复途径的能力。巨噬细胞(Mφ),最丰富的哨兵
肺中的免疫细胞类型是损伤后恢复组织-流体稳态所必需的,但是
修复性Mφ亚群的身份以及它们是如何产生的仍然难以捉摸。这里有
发现肺泡Mφ(AMφ)细胞群的一个亚群,它是维持肺内液体平衡所必需的
并诱导损伤后的组织修复。我们的支持性数据表明:1)cAMP反应的丧失
髓系细胞(Creb/LyzM小鼠)中的元件结合(CREB)蛋白表达阻滞了AMφ亚群
在前AM φ阶段,导致AMφ生成减少和肺血管通透性增加
2)Creb/LyzM小鼠在LPS攻击后未能解决损伤,并且在假单胞菌感染后更快地死亡。
铜绿假单胞菌感染; 3)转录组测序(RNAseq)和染色质可及性分析(ATACseq)
流式细胞分选的CREB缺失的AMφ具有显著改变的基因表达和染色质重塑;和4)CREB是
抑制丙酮酸脱氢酶复合物(PDC)过量产生核乙酰辅酶A所需
通过合成丙酮酸脱氢酶激酶4(PDK 4)。根据这些挑衅性的初步数据,
在目标1中,我们将检验CREB转录促进这种屏障分化的假设
修复性AMφ亚群。在目标#2中,我们将研究CREB调节修复性AMφ产生
通过控制组蛋白的表观遗传修饰,从而导致AMφ基因转录。在这里,我们将
提出了CREB的转录活性是上调PDK 4表达所必需的新概念,
这反过来又阻止了它的靶点PDC从线粒体到细胞核的转运,从而抑制了
过量的核乙酰辅酶A生成和限制组蛋白的表观遗传修饰,导致基因
诱导屏障修复性AMφ群体的转录。这些研究将采用严格的多-
组学方法(单细胞RNA、ATAC和芯片测序)和基因改变小鼠中的功能测定
包括Rosa-CrebCxcxr 3-ERT小鼠(其中CREB在单核细胞/间质巨噬细胞中条件性缺失)
以确定CREB转录活性在产生修复性AMφ群体中的作用。理解
如何产生这种屏障修复性AM受体亚群,应该可以增强这种亚群的分化,
通过药理学或遗传学手段在损伤过程中减少亚群,从而降低ALI和相关疾病的死亡率。
条件
项目成果
期刊论文数量(0)
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DOLLY MEHTA其他文献
DOLLY MEHTA的其他文献
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{{ truncateString('DOLLY MEHTA', 18)}}的其他基金
Targeting mechanisms activating ion-channel for preventing acute lung injury
激活离子通道的靶向机制预防急性肺损伤
- 批准号:
10659781 - 财政年份:2023
- 资助金额:
$ 15.99万 - 项目类别:
The Lung Endothelium as an Instructive Niche for the Innate Immune System during Vascular Injury
肺内皮细胞作为血管损伤期间先天免疫系统的指导性生态位
- 批准号:
10494611 - 财政年份:2022
- 资助金额:
$ 15.99万 - 项目类别:
S1PR1 Mislocalization in Lung Endothelium Regulates Innate Immune Function and Mediates Inflammatory Lung Injury
S1PR1 在肺内皮细胞中的错误定位调节先天免疫功能并介导炎症性肺损伤
- 批准号:
10706510 - 财政年份:2022
- 资助金额:
$ 15.99万 - 项目类别:
The Lung Endothelium as an Instructive Niche for the Innate Immune System during Vascular Injury
肺内皮细胞作为血管损伤期间先天免疫系统的指导性生态位
- 批准号:
10706498 - 财政年份:2022
- 资助金额:
$ 15.99万 - 项目类别:
S1PR1 Mislocalization in Lung Endothelium Regulates Innate Immune Function and Mediates Inflammatory Lung Injury
S1PR1 在肺内皮细胞中的错误定位调节先天免疫功能并介导炎症性肺损伤
- 批准号:
10494616 - 财政年份:2022
- 资助金额:
$ 15.99万 - 项目类别:
CREB Instruction of Macrophage Fate and Lung fluid homeostasis
CREB对巨噬细胞命运和肺液稳态的指导
- 批准号:
10305990 - 财政年份:2021
- 资助金额:
$ 15.99万 - 项目类别:
CREB Programming of Alveolar Macrophage Population and Inflammatory Lung Injury
肺泡巨噬细胞群和炎症性肺损伤的 CREB 编程
- 批准号:
10491070 - 财政年份:2021
- 资助金额:
$ 15.99万 - 项目类别:
CREB Programming of Alveolar Macrophage Population and Inflammatory Lung Injury
肺泡巨噬细胞群和炎症性肺损伤的 CREB 编程
- 批准号:
10701930 - 财政年份:2021
- 资助金额:
$ 15.99万 - 项目类别:
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