Endothelial Instruction of Macrophage Fate in Inflammatory Lung Injury
Endothelial Instruction of Macrophage Fate in Inflammatory Lung Injury
批准号:
10701931
负责人:
Jalees Rehman
金额:
$42.8万
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:
未结题
起止时间:
2021-09-20 至 2026-06-30
关键词:
ATP Citrate (pro-S)-LyaseAcetyl Coenzyme AAcute Lung InjuryAdultAlveolar MacrophagesAnti-Inflammatory AgentsBindingBlood VesselsCell LineCell NucleusCellsCharacteristicsCollaborationsComplexDataEndothelial CellsEndotheliumEnzymesEpigenetic ProcessG-Protein-Coupled ReceptorsGenerationsGenetic TranscriptionHistone AcetylationHomeostasisHumanITGAM geneImageImmuneIn VitroIndividualInflammationInflammatoryInjuryInstructionLeucine-Rich RepeatLicensingLifeLipoprotein ReceptorLoxP-flanked alleleLungMacrophageMeasuresMediatingMetabolicMetabolismMitochondriaModelingModificationMusNADHPatientsPhenotypePopulationProcessProteinsRegulationResolutionRespirationRoleSignal TransductionTestingTissuesTranscription CoactivatorTranscriptional ActivationTranscriptional RegulationWNT Signaling Pathwaybeta catenincell typecofactorepigenetic regulationepigenomehigh resolution imagingin vivointerstitiallung injurymetabolomicsmigrationmitochondrial metabolismmonocytemouse modeloptogeneticsprenatalprogramsreceptorresponse to injurysingle-cell RNA sequencingsynthetic biologytissue injurytissue repairtranscriptomics
中文摘要
项目概要/摘要
研究表明,巨噬细胞在应对炎症和组织损伤方面的作用比
先前认识到的,例如促进炎症消退、组织修复和恢复组织稳态
这种对巨噬细胞可塑性的认识将焦点从 M1 和 M2 的简单概念转移开
二分法。项目 3 重点描述介导单核细胞转变为组织巨噬细胞的信号和
它们在急性肺损伤(ALI)的组织修复中具有潜在的重要作用。由于肺内皮是
单核细胞迁移到组织中,内皮细胞(EC)可能会改变下游巨噬细胞
表型,因此细胞之间的相互作用可能产生重大影响。项目3将描绘
ECs 指导巨噬细胞的产生机制及其在解决 ALI 中的作用。我们将解决
基本问题包括:介导向修复性巨噬细胞转变的 EC 信号是什么
人口?巨噬细胞中的哪些信号反过来将细胞转化为修复组织?什么是表观遗传和
这些表型转变的巨噬细胞的转录组特征?在项目 3 中,我们将测试以下假设:
肺内皮通过 Wnt 信号传导通过修饰线粒体介导巨噬细胞表型转变
启动特定转录程序的代谢和表观基因组。在目标 1 中,我们将定义以下角色:
内皮 Wnt 信号传导调节肺中单核细胞向巨噬细胞的分化。在这里我们将
确定源自 EC 的 Wnt 信号调节因子 Rspondin 3 (Rspo3) 在信号转导中的作用
单核细胞到肺巨噬细胞。在目标 2 中,我们将确定代谢重编程和表观遗传的作用
巨噬细胞在介导表型转变中的修饰,从而减少肺损伤的程度
并推动其解决。
英文摘要
PROJECT SUMMARY/ABSTRACT
Studies have shown much broader roles for macrophages in responding to inflammation and tissue injury than
previously recognized, such as promoting inflammation resolution, tissue repair and restoring tissue homeostasis
and this recognition of macrophage plasticity has shifted the focus away from the simple notion of M1 and M2
dichotomies. Project 3 focuses on delineating the signals mediating monocyte transition to tissue macrophages and
their potentially essential role in tissue repair in acute lung injury (ALI). As the lung endothelium is the entry point of
the monocytes transmigrating into tissue, endothelial cells (ECs) may modify the downstream macrophage
phenotype, and thus the interaction between cells may be of great consequence. Project 3 will delineate
mechanisms of generation of how ECs instruct macrophages and their role in resolving ALI. We will address
fundamental questions including: What are the EC signals mediating transition to the reparative macrophage
populations? What signals in macrophages in turn convert the cells to repair tissue? What are the epigenetic and
transcriptomic features of these phenotype-shifted macrophages? In Project 3 we will test the hypothesis that the
lung endothelium via Wnt signaling mediates macrophage phenotype transition through modifying mitochondrial
metabolism and epigenome that initiates specific transcriptional programs. In Aim 1, we will define the role of
endothelial Wnt signaling in regulating the differentiation of monocytes to macrophages in lungs. Here we will
determine the role of the Wnt signaling regulator Rspondin 3 (Rspo3) derived from ECs in signaling the transition of
monocytes to lung macrophages. In Aim 2, we will determine the role of metabolic reprogramming and epigenetic
modifications of macrophages in mediating phenotype transition and thereby reducing the extent of lung injury as
well as promoting its resolution.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Mitochondrial Dysfunction in the Endothelium as a Mediator of Inflammatory Injury
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批准号:10494618
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项目类别:
-
资助金额:$44.37万
-
财政年份:2022
-
负责人:Jalees Rehman
-
依托单位:
Mitochondrial Dysfunction in the Endothelium as a Mediator of Inflammatory Injury
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批准号:10706520
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项目类别:
-
资助金额:$42.85万
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财政年份:2022
-
负责人:Jalees Rehman
-
依托单位:
Endothelial Instruction of Macrophage Fate in Inflammatory Lung Injury
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批准号:10491076
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项目类别:
-
资助金额:$42.8万
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财政年份:2021
-
负责人:Jalees Rehman
-
依托单位:
Endothelial Instruction of Macrophage Fate in Inflammatory Lung Injury
-
批准号:10170865
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项目类别:
-
资助金额:$30.14万
-
财政年份:2021
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负责人:Jalees Rehman
-
依托单位:
Integration Free IPS Cells-Derived Progenitors for Cardiac Regeneration
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批准号:9441040
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项目类别:
-
资助金额:$73.41万
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财政年份:2015
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负责人:Jalees Rehman
-
依托单位:
Integration Free IPS Cells-Derived Progenitors for Cardiac Regeneration
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批准号:9226014
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项目类别:
-
资助金额:$74.91万
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财政年份:2015
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负责人:Jalees Rehman
-
依托单位:
The role of mitochondria in embryonic stem cells.
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批准号:8323300
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项目类别:
-
资助金额:$29.99万
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财政年份:2011
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负责人:Jalees Rehman
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依托单位:
The role of mitochondria in embryonic stem cells.
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批准号:8653967
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项目类别:
-
资助金额:$29.41万
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财政年份:2011
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负责人:Jalees Rehman
-
依托单位:
The role of mitochondria in embryonic stem cells.
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批准号:8108690
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项目类别:
-
资助金额:$30.21万
-
财政年份:2011
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负责人:Jalees Rehman
-
依托单位:
The role of mitochondria in embryonic stem cells.
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批准号:8463217
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项目类别:
-
资助金额:$28.38万
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财政年份:2011
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负责人:Jalees Rehman
-
依托单位:
The Effects of Reactive Oxygen Species on Endothelial Progenitor Cells
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批准号:7586496
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项目类别:
-
资助金额:$13.3万
-
财政年份:2006
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负责人:Jalees Rehman
-
依托单位:
Reactive Oxygen Species on Endothelial Progenitor Cells
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批准号:7079710
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项目类别:
-
资助金额:$13.3万
-
财政年份:2006
-
负责人:Jalees Rehman
-
依托单位:
The Effects of Reactive Oxygen Species on Endothelial Progenitor Cells
-
批准号:7795825
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项目类别:
-
资助金额:$13.3万
-
财政年份:2006
-
负责人:Jalees Rehman
-
依托单位:
The Effects of Reactive Oxygen Species on Endothelial Progenitor Cells
-
批准号:7220593
-
项目类别:
-
资助金额:$13.3万
-
财政年份:2006
-
负责人:Jalees Rehman
-
依托单位:
The Effects of Reactive Oxygen Species on Endothelial Progenitor Cells
-
批准号:7357460
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项目类别:
-
资助金额:$13.3万
-
财政年份:2006
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负责人:Jalees Rehman
-
依托单位:
Metabolic Regulation of Endothelial Barrier Restoration Following Vascular Injury
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批准号:9151431
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项目类别:
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资助金额:$33.95万
-
财政年份:--
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负责人:Jalees Rehman
-
依托单位:
Metabolic Regulation of Endothelial Barrier Restoration Following Vascular Injury
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批准号:9324311
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项目类别:
-
资助金额:$33.95万
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财政年份:--
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负责人:Jalees Rehman
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依托单位:
海外基金