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
项目成果
期刊论文数量(0)
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DOLLY MEHTA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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