Neutrophils play a pivotal role in vascular aging
Neutrophils play a pivotal role in vascular aging
批准号:
10637703
负责人:
Zhen Yue Jiang
金额:
$58.34万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-03-22 至 2027-02-28
关键词:
AcetylationAgingAmilorideAnimalsAortaB-LymphocytesBMP2 geneBlood PressureBlood VesselsC57BL/6 MouseCXC ChemokinesCardiovascular DiseasesCell Adhesion MoleculesCellsChronicCytoplasmic GranulesDNA BindingDataDeacetylaseDevelopmentDietDiseaseElastasesEndotheliumEventExtracellular MatrixExtravasationFatty acid glycerol estersFemaleFibrosisFructoseHumanImmuneIn VitroInfiltrationInflammationInflammatoryInjuryKnock-outKnockout MiceLeucocytic infiltrateLeukocyte ElastaseLeukocytesLongevityMADH2 geneMeasuresMedialMediatingMediatorMolecularMusNeutrophil InfiltrationNuclear TranslocationObesityOralOxidantsPAR-2 ReceptorPathologicPathway interactionsPeptide HydrolasesPermeabilityPhenotypePhosphotransferasesPhysiologic pulsePlayPrevalenceProcessProductionRegulationReportingResistanceRoleSIRT1 geneSerine ProteaseSignal PathwaySignal TransductionSiteSmooth MuscleSmooth Muscle MyocytesTestingTherapeutic EffectTissuesTransforming Growth Factor betaVascular DementiaVascular Endothelial CellVascular EndotheliumVascular PermeabilitiesVascular Smooth MuscleVascular remodelingage relatedagedarterial stiffnesscalcificationchemokine receptorconnective tissue growth factorepithelial Na+ channelfeedingin vivomalemigrationmouse modelneutrophilneutrophil elastase inhibitornovelnovel therapeutic interventionobesogenicosteogenicprogenitorprotective effecttissue injuryvascular endothelium permeabilityvascular injury
中文摘要
摘要
英文摘要
Abstract
Arterial stiffness is a hallmark of vascular aging and is related to increased cardiovascular disease events and
vascular dementias. Inflammatory damage and extracellular matrix remodeling have been proposed as the major
pathological causes of vascular injury and arterial stiffness. However, the molecular mechanisms that initiate
and propagate aging-related pathological changes in large blood vessels remain unclear. Here, we propose to
study the role of neutrophil elastase (NE), a neutrophil-specific protease, in initiating vascular leakage,
inflammation and fibrosis in aged mice both with and without obesity. Neutrophils are the most abundant
leukocytes, have a short lifespan, and play a critical role in initiating tissue damage and inflammation. Our data
demonstrated (1) that pulse wave velocity (PWV), the primary parameter of arterial stiffness, was decreased in
NE knockout (NEKO) mice compared to their wild-type littermates, and (2) that NEKO mice were resistant to
aging-related inflammation, fibrosis and calcification in the aorta. We also observed that NE has potent effects
on increasing vascular endothelial permeability and enhancing aortic smooth muscle cell fibrogenic and
osteogenic phenotypic switch. Further, NE regulates neutrophil proinflammatory phenotype by degrading
longevity regulator Sirtuin 1 (Sirt1). Based on our preliminary data, we hypothesize that pro-inflammatory
neutrophils interact with blood vessels, causing vascular damage and remodeling through the release of NE.
The latter contributes to the increased vascular permeability, fibrotic remodeling and calcification in the blood
vessels. Thus, inhibiting NE may lead to protective effects on aging-related vascular damage, fibrotic remodeling,
calcification, and subsequent arterial stiffness. The objective of this RO1 proposal is to explore how neutrophils
and NE regulate inflammatory remodeling in the arterial wall during the aging process with or without feeding of
an obesogenic diet. We will explore whether NE contributes to vascular aging by activating protease-activated
receptor 2 (PAR2) and epithelium sodium channel (ENaC) signaling pathways in vascular endothelial cells and
vascular smooth muscle cells with both in vitro and in vivo studies. Also, we will examine the role of the NE–Sirt1
signaling pathway in the regulation of neutrophil phenotype and aging-related vascular injury and remodeling in
mice. Finally, we will evaluate potential therapeutic effects of a selective NE inhibitor on aging-related arterial
stiffness in mice. Successful completion of this project will provide a novel therapeutic strategy for vascular aging
and related diseases.
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会议论文
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批准号:10477430
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项目类别:
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资助金额:$41.52万
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财政年份:2020
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负责人:Zhen Yue Jiang
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依托单位:
Neutrophil elastase in obesity-related fatty liver diseases
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批准号:10099752
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项目类别:
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资助金额:$41.93万
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财政年份:2020
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依托单位:
Neutrophil elastase in obesity-related fatty liver diseases
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资助金额:$41.66万
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Neutrophil elastase in obesity-related fatty liver diseases
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资助金额:$35.06万
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Phosphoprotein CDP138 regulates glucose metabolism
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批准号:8852603
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资助金额:$35.6万
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依托单位:
Phosphoprotein CDP138 regulates glucose metabolism
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批准号:8775218
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项目类别:
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资助金额:$30.47万
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财政年份:2012
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依托单位:
Phosphoprotein CDP138 regulates glucose metabolism
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批准号:8750861
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资助金额:$26.86万
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财政年份:2012
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Phosphoprotein CDP138 regulates glucose metabolism
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批准号:8466967
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项目类别:
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资助金额:$8.93万
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财政年份:2012
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负责人:Zhen Yue Jiang
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依托单位:
Phosphoprotein CDP138 regulates glucose metabolism
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批准号:8222368
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项目类别:
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资助金额:$42.41万
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财政年份:2012
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High content screening assay for activators of glucose transporter GLUT4
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财政年份:2010
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依托单位:
海外基金