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
基本信息
- 批准号:10706498
- 负责人:
- 金额:$ 233.93万
- 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:2022-09-20 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AKT1 geneAcute Lung InjuryAcute Respiratory Distress SyndromeAddressAdherens JunctionAlveolarAngiopoietin-2AreaArteriesAutomobile DrivingBacterial InfectionsBiogenesisBloodBlood VesselsBrainCOVID-19 pandemicCalcium SignalingCause of DeathCell AdhesionCell membraneCellsCollaborationsComplexCuesDataDefense MechanismsDevelopmentDiseaseDisease ProgressionEdemaEndoplasmic ReticulumEndothelial CellsEndotheliumEnvironmentEpigenetic ProcessExposure toFOXO1A geneFoundationsGene Expression RegulationGenerationsGenetic TranscriptionGoalsHealthHeartHomeostasisHost DefenseHumanImageImmuneImmune responseImmune systemImmunityImmunoglobulin binding proteinsImpairmentInfectionInflammationInflammatoryInjuryInnate Immune ResponseInnate Immune SystemLeadershipLeukocytesLigationLiquid substanceLungMediatingMembraneMetabolismMitochondriaMusNatural regenerationOrganOrganellesPINK1 genePathogenesisPathogenicityPathway interactionsPatientsPhosphotransferasesPhysiologyPopulationProcessProteinsPulmonary InflammationRegulationResolutionRespiratory FailureRing Finger DomainRoleSignal PathwaySignal TransductionSupportive careSurfaceTennisTestingTimeTraumaUbiquitinationUp-RegulationVariantVascular Endothelial CellVeinsVentilatorVirus DiseasesWorkalveolar epitheliumcadherin 5cellular imagingcheckpoint modulationcourteffective therapyendothelial regenerationformyl peptideimmune activationimmune functionimmunoregulationinflammatory lung diseaseinnate immune functioninnovationinorganic phosphateintravital imaginglung imaginglung injurylung repairmigrationmitochondrial dysfunctionmonolayermortalityneutrophilnew therapeutic targetnovelpreventprogramspulmonary functionreceptorresponserestorationspatiotemporalsuccesssynergismtargeted treatmenttraffickingtranscriptome sequencingtranscriptomicstwo-photonubiquitin-protein ligaseultra high resolutionvascular injury
项目摘要
ABSTRACT OF PROGRAM
The loss of lung vascular barrier integrity in settings as diverse as trauma and bacterial or viral infections is a
hallmark of acute lung injury (ALI) and its serious variant ARDS. ALI is characterized by protein-rich edema and
ultimately respiratory failure. Targeted therapies remain an urgent unmet need. It is now becoming increasingly
clear that the lung endothelium is a complex monolayer, almost an organ itself, consisting of not only alveolar
endothelial cells (EC) but also specific EC populations found in pulmonary microvessels, arteries and veins.
Recently, we have shown using RNA-sequencing that the lung EC demonstrate significant upregulation of genes
involved in processes related to immune function such as leukocyte cell adhesion, leukocyte migration, and
regulation of immune system. This finding was consistent with lung EC being continuously exposed to the
external environment, unlike EC in other organs such as the brain or heart. Studying this immune regulatory
function of the lung endothelium is crucial for understanding how the EC controls immunity and the host defense
function of lungs, and also how its dysregulation or impairment of the immune response leads to pathogenesis
of ALI. This Program builds on the extraordinary success of a previous 20-year entity, evident by our
accomplishments. We have helped establish the lung endothelium as a node for understanding the lung’s
response to infection and injury and our work has led to better understanding of ways of treating endothelial
barrier breakdown in lungs. This revised application, focusing on the enigmatic innate immune function of the
lung endothelium, is built on foundations of synergy and collaborations. Our Supporting data show the central
role of the lung endothelium in driving inflammatory lung injury, and at the same time provides clues that will lead
to new lung injury targeting therapies. Project 1 will test the hypothesis that the post-translationally modified
endoplasmic reticulum-localized spinghosine-1-phosphate receptor S1PR1 in an unexpected manner
reprograms lung endothelium to activate a signaling cascade that induces inflammatory lung injury. Project 2
will test the hypothesis that a novel lung endothelial cell expressed ubiquitin E3 ligase CHFR (checkpoint with
fork-head and ring finger domain) identified by us regulates VE-cadherin-mediated endothelial barrier integrity
and lung’s innate immune function. Targeting CHFR thus holds promise for preventing inflammatory lung injury.
Project 3 will test the hypothesis that lung endothelial mitochondrial dysfunction and induction of mitophagy
regulate endothelial regeneration and serve as a key check point for restoring homeostasis and preventing
inflammatory injury. These Projects are supported by innovative scientific Cores (Epigenetics and
Transcriptomics (Core B), Cellular Imaging (Core C), and Intravital Imaging and Physiology (Core D) that
will make it possible to rigorously address the innate immune function of the lung endothelium and its role in
orchestrating restoration of homeostasis. We hope to unravel the innate immune function of the lung
endothelium, thus providing strategies to develop new targeted therapies against ALI and ARDS.
程序摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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:
$ 233.93万 - 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:
$ 233.93万 - 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:
$ 233.93万 - 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:
$ 233.93万 - 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:
$ 233.93万 - 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:
$ 233.93万 - 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:
$ 233.93万 - 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:
10625859 - 财政年份:2021
- 资助金额:
$ 233.93万 - 项目类别:
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