REDOX REGULATION OF eNOS SIGNALING PATHWAYS IN VASCULAR ENDOTHELIUM
血管内皮细胞 eNOS 信号通路的氧化还原调节
基本信息
- 批准号:8250446
- 负责人:
- 金额:$ 41.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-04-01 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:5&apos-AMP-activated protein kinase7,8-dihydrobiopterinAMP-activated protein kinase kinaseAffectBiogenesisBiological AvailabilityBiological MarkersBiopterinBlood VesselsCalciumCalmodulinCardiovascular AgentsCardiovascular DiseasesCatalysisCaveolaeCaveolinsClinicalCysteineDiabetes MellitusEmployee StrikesEndothelial CellsEnergy MetabolismEnzyme InhibitionEnzymesEquilibriumFunctional disorderGenerationsHomeostasisHydrogen PeroxideHydroxymethylglutaryl-CoA Reductase InhibitorsInstructionLeadLinkMediatingMembrane MicrodomainsMetabolicMetabolismMitochondriaMolecularMusNADPNitric OxideNitric Oxide SynthaseNitrogenNitroglycerinOxidation-ReductionOxidative StressOxidoreductaseOxygenPathway interactionsPhosphorylationPhysiologyPlatelet aggregationPost-Translational Protein ProcessingProductionProtein IsoformsProtein KinaseProtein SProteinsProto-Oncogene Proteins c-aktRNA InterferenceReactive Nitrogen SpeciesReactive Oxygen SpeciesRecyclingRegulationRoleSeriesSignal PathwaySignal TransductionSignaling ProteinSmall Interfering RNASulfhydryl CompoundsSuperoxidesThioredoxinVascular DiseasesVascular Endothelial CellVascular EndotheliumVasodilationadductcaveolin 1cofactorglutathione peroxidasehuman NOS3 proteinknock-downoxidationprogramsprotein functionresearch studyresponsescaffoldtetrahydrobiopterin
项目摘要
PROJECT SUMMARY (See instructions):
The endothelial isoform of nitric oxide synthase (eNOS) is a key determinant of vascular homeostasis and
endothelial cell metabolism. eNOS catalysis involves several redox-active cofactors, and NO itself can
interact with reactive oxygen species. The bioavailability of endothelium-derived NO is impaired in vascular
disease states associated with, increased oxidative stress. We hypothesize that redox regulation ofthe eNOS
pathway represents a critical determinant of NO- and ROS-dependent signaling and metabolic regulation in
vascular endothelial cells. The proposed studies have important points of intersection with experimental
plans proposed by other Projects in this Program. eNOS catalysis involves several redox-active cofactors;
changes in intracellular redox state affect the concentrations of these key cofactors, and lead to alterations in
eNOS-modulated responses. The formation of cellular NO adducts is influenced by reactive nitrogen and
reactive oxygen species and by the cellular thiol redox state. Phosphorylation of eNOS by the AMP-activated
protein kinase (AMPK) is influenced by reactive oxygen species, providing an important link between
oxidative stress, eNOS signaling, and endothelial cell metabolism. Statins also activate AMPK and modulate
endothelial ROS production. eNOSJs targeted to signal-transducing membrane microdomains termed
caveolae, where the enzyme interacts with the scaffolding/signaling protein caveolin-1. We discovered that
siRNA-mediated knockdown of caveolin leads to a striking increase in ROS production from endothelial cells,
and found that caveolin-1-/- mice show dramatic increases in oxidative stress. eNOS-caveolin interactions
are modulated by statins, yet the roles of statins in modulation of redox pathways involving eNOS remain
incompletely understood. Experiments proposed in Specific Aim 1 will identify the mechanisms whereby
altered biopterin and thiol metabolism affects eNOS post-translational modifications, subcellular targeting,
and ROS generation. Experiments in Specific Aim 2 will determine the mechanisms whereby caveolin,
statins, and reactive oxygen species modulate AMP-activated protein kinase (AMPK) signaling to eNOS.
项目概述(见说明):
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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Thomas Michel其他文献
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{{ truncateString('Thomas Michel', 18)}}的其他基金
Hydrogen peroxide in endothelial function and dysfunction
过氧化氢在内皮功能和功能障碍中的作用
- 批准号:
10320952 - 财政年份:2021
- 资助金额:
$ 41.05万 - 项目类别:
Dynamic tissue-specific modulation of redox stress using chemogenetics
利用化学遗传学对氧化还原应激进行动态组织特异性调节
- 批准号:
10393690 - 财政年份:2021
- 资助金额:
$ 41.05万 - 项目类别:
Dynamic tissue-specific modulation of redox stress using chemogenetics
利用化学遗传学对氧化还原应激进行动态组织特异性调节
- 批准号:
10214064 - 财政年份:2021
- 资助金额:
$ 41.05万 - 项目类别:
Hydrogen peroxide in endothelial function and dysfunction
过氧化氢在内皮功能和功能障碍中的作用
- 批准号:
10543765 - 财政年份:2021
- 资助金额:
$ 41.05万 - 项目类别:
Chemogenetic approaches to define the roles of redox dysfunction in the cardiomyopathy of aging
化学遗传学方法确定氧化还原功能障碍在衰老心肌病中的作用
- 批准号:
9922852 - 财政年份:2019
- 资助金额:
$ 41.05万 - 项目类别:
ANIMAL MODELS OF REDOX METABOLISM AND ARTERIAL DYSFUNCTION
氧化还原代谢和动脉功能障碍的动物模型
- 批准号:
8250450 - 财政年份:2011
- 资助金额:
$ 41.05万 - 项目类别:
REDOX REGULATION OF eNOS SIGNALING PATHWAYS IN VASCULAR ENDOTHELIUM
血管内皮细胞 eNOS 信号通路的氧化还原调节
- 批准号:
7975784 - 财政年份:2010
- 资助金额:
$ 41.05万 - 项目类别:
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