Project 5: ROS, Glutathione and Vascular Response to Diesel Exhaust
Project 5: ROS, Glutathione and Vascular Response to Diesel Exhaust
批准号:
8278533
负责人:
Terrance J Kavanagh
金额:
$28.75万
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
项目状态:
已结题
起止时间:
2011-06-01 至 2013-05-31
关键词:
Air PollutionAngiotensin IIAntioxidantsApoptosisBindingBiochemicalBlood VesselsCandidate Disease GeneCardiac MyocytesCardiovascular DiseasesCardiovascular PhysiologyCardiovascular systemCatalytic DomainCellsChromosome MappingConsumptionCultured CellsCysteineDiesel ExhaustDoctor of PhilosophyDoppler UltrasoundEndothelial CellsEndothelin-1EndotheliumEnzymesEventExposure toFunctional disorderGCLC geneGCLM geneGene ExpressionGenerationsGenesGeneticGenetic DeterminismGenetic PolymorphismGlutamate-Cysteine LigaseGlutamatesGlutathioneGlycineHeat shock proteinsHomeostasisHumanHydrogen PeroxideHydroxyl RadicalIn VitroInbred Strains MiceInflammatoryIschemiaLigaseLigase GeneLipid PeroxidesMapsMetabolic ControlMetabolismMicroscopyMitochondriaMusMyocardial InfarctionNADPH OxidaseNitric OxideNitric Oxide SynthaseOxidation-ReductionOxidative StressPerformancePeroxonitritePredispositionPreparationProcessProductionQuantitative Trait LociReactive Oxygen SpeciesRecombinant Inbred StrainRegulationRiskRisk FactorsRoleSerumSignal TransductionSingle Nucleotide PolymorphismSmooth Muscle MyocytesSulfhydryl CompoundsSuperoxidesThrombosisTransgenic MiceUltrasonicsUmbilical veinVasoconstrictor AgentsVasodilationVasodilator AgentsVasomotoraqueouscell injurycell typechemokinecofactorcomparativecytokinecytotoxicityin vivointerestmouse modelnitrationoxidationparticlepreventprogramsprotein functionresponsestress proteintetrahydrobiopterintooltraffickingvasoconstriction
中文摘要
暴露在与交通有关的空气污染中,如柴油废气(DE),与
多种细胞类型中的ROS水平。这些ROS包括超氧阴离子
自由基、过氧化氢、过氧化脂质和羟基自由基。ROS可能会对细胞产生有害影响,
但已知它们也参与正常的跨膜信号和代谢控制。
心血管系统。例如,两种有效的血管收缩药,血管紧张素II和内皮素-1,可以
通过增加平滑肌细胞NADPH氧化酶产生的ROS,从而导致细胞内
细胞内超氧化物和过氧化氢的浓度。超氧化物可以与一氧化氮(NO)结合
形成过氧亚硝酸盐,这会导致细胞损伤,但也限制了可用于血管松弛的一氧化氮的量。
以这种方式产生的ROS还可以氧化四氢生物蝶呤,这是NO的必要辅助因子。
合酶(NOS),导致NOS解偶联,产生更多的超氧化物和过氧亚硝酸根。
超氧化物以这种方式消耗NO会导致血管收缩。因此,RO能够影响
心血管功能和血管反应性。谷胱甘肽(GSH)是一种含量丰富的非蛋白硫醇
它是一种有效的ROS清除剂,包括过氧化氢、过氧化脂质,重要的是,
过氧酸盐(ONOO-)。谷胱甘肽是一种以毫摩尔浓度存在于大多数细胞中的三肽硫醇。第一个和
谷胱甘肽合成的限速步骤是由谷氨酸半胱氨酸连接酶(GCL)执行的,该酶是
由两个亚基组成,一个催化亚基(GCLC)和一个修饰物或调节亚单位(GCLM)。
重要的是,GCLC和GCLM中的单核苷酸多态(SNPs)已经被证明是
在心肌梗死以及控制人体血管反应性方面很重要。在这个项目中,我们将
采用比较研究的方法,探讨GCL产生这种效应的原因。我们将使用鼠标
GCL差异表达和活性模型研究其在DE诱导的血管改变中的作用
反应性2),使用这些小鼠和人类的培养内皮细胞来研究潜在的
GSH和DE诱导内皮细胞NO生成调节的生化事件;
描述基因定义的近交系小鼠对DE的血管反应具有变异性的特征,
并确定与这些基因相关的单核苷酸多态(SNPs)和数量性状基因座
小鼠的变化。使用这些工具,我们将定义GSH合成在DE诱导的
血管反应性,研究潜在的病理生理机制,并定位和识别基因
DE引起血管反应性改变的决定因素。这些候选基因随后将被引用
项目1和项目2将进一步评估它们作为DE诱导血管的潜在遗传因素
人类的反常现象。
英文摘要
Exposure to traffic-related air pollution such as diesel exhaust (DE) is associated with an increase in the
level of reactive oxygen species (ROS) in multiple cell types. These ROS include the superoxide anion
radical, hydrogen peroxide, lipid peroxides and hydroxyl radical. ROS can have deleterious effects on cells,
but they are also known to be involved in normal transmembrane signaling and metabolic control in the
cardiovascular system. For instance, two potent vasoconstrictors, angiotensin II and endothelin-1, can
increase production of ROS by smooth muscle cell NADPH oxidase, thus causing an increase in the
intracellular concentrations of superoxide and hydrogen peroxide. Superoxide can bind to nitric oxide (NO)
to form peroxynitrite, which can cause cellular injury, but also limit the amount of NO available for vasorelaxation.
ROS generated in this way can also oxidize tetrahydrobiopterin, a necessary cofactor for NO
synthase (NOS), resulting in uncoupling of NOS and production of more superoxide and peroxynitrite.
Consumption of NO by superoxide in this way can result in vasoconstriction. ROS are thus able to influence
cardiovascular performance and vascular reactivity. Glutathione (GSH) is an abundant non-protein thiol
which is a potent scavenger of ROS, including hydrogen peroxide, lipid peroxides, and importantly,
peroxitrite (ONOO-). GSH is a tripeptide thiol present in millimolar concentrations in most cells. The first and
rate-limiting step in GSH synthesis is carried out by the enzyme glutamate cysteine ligase (GCL), which is
composed of two subunits, a catalytic subunit (GCLC) and a modifier or regulatory subunit (GCLM).
Importantly, single nucleotide polymorphisms (SNPs) in both GCLC and GCLM have been shown to be
important in myocardial infarction, as well as controlling vascular reactivity in humans. In this project, we will
investigate the reasons for this effect of GCL by using a comparative approach. We will 1) use mouse
models of differential GCL expression and activity to investigate its role in DE-induced changes in vascular
reactivity 2), use cultured endothelial cells from these mice and from humans to investigate the underlying
biochemical events responsible for GSH and DE-induced modulation of endothelial NO production; and 3)
characterize genetically defined inbred strains of mice that have variability in their vascular responses to DE,
and identify single nucleotide polymorphisms (SNPs) and quantitative trait loci that are associated with these
changes in mice. Using these tools we will define the role of GSH synthesis in DE-induced changes in
vascular reactivity, investigate the underlying pathophysiological mechanisms, and map and identify genetic
determinants of DE-induced changes in vascular reactivity. These candidate genes will then be referred to
Projects 1 and 2 where they will be further evaluated as potential genetic factors in DE-induced vascular
abnormalities in humans.
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Pilot Project Program
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批准号:8830359
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项目类别:
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资助金额:$20.27万
-
财政年份:2015
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负责人:Terrance J Kavanagh
-
依托单位:
Pilot Project Program
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批准号:8650858
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项目类别:
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资助金额:$20.25万
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财政年份:2014
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负责人:Terrance J Kavanagh
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依托单位:
Core 2: Administration Core
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批准号:8274473
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项目类别:
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资助金额:$6.86万
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财政年份:2011
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负责人:Terrance J Kavanagh
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依托单位:
Linking the physical and chemical characteristics of Qdots to their toxicity
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批准号:8332607
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项目类别:
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资助金额:$6.6万
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财政年份:2010
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负责人:Terrance J Kavanagh
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依托单位:
Linking the physical and chemical characteristics of Qdots to their toxicity
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批准号:8464705
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项目类别:
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资助金额:$106.21万
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财政年份:2010
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负责人:Terrance J Kavanagh
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依托单位:
Linking the physical and chemical characteristics of Qdots to their toxicity
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批准号:8675245
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项目类别:
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资助金额:$104.74万
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财政年份:2010
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负责人:Terrance J Kavanagh
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依托单位:
Linking the physical and chemical characteristics of Qdots to their toxicity
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批准号:8016872
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项目类别:
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资助金额:$115.38万
-
财政年份:2010
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负责人:Terrance J Kavanagh
-
依托单位:
Linking the physical and chemical characteristics of Qdots to their toxicity
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批准号:8258515
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项目类别:
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资助金额:$3.01万
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财政年份:2010
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负责人:Terrance J Kavanagh
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依托单位:
Linking the physical and chemical characteristics of Qdots to their toxicity
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批准号:8274474
-
项目类别:
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资助金额:$109.01万
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财政年份:2010
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负责人:Terrance J Kavanagh
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依托单位:
Core 2: Administration Core
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批准号:8066922
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项目类别:
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资助金额:$3.5万
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财政年份:2010
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负责人:Terrance J Kavanagh
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依托单位:
Project 2: In vivo Studies: Characterize absorption, distribution, metabolism, el
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批准号:8066918
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项目类别:
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资助金额:$31.56万
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财政年份:2010
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负责人:Terrance J Kavanagh
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依托单位:
Linking the physical and chemical characteristics of Qdots to their toxicity
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批准号:8147704
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项目类别:
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资助金额:$110.97万
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财政年份:2010
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负责人:Terrance J Kavanagh
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依托单位:
Modulation of Qdot nanoparticle toxicity by glutathione in GCL transgenic mice
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批准号:7341245
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项目类别:
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资助金额:$45.45万
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财政年份:2007
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负责人:Terrance J Kavanagh
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依托单位:
Modulation of Qdot nanoparticle toxicity by glutathione in GCL transgenic mice
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批准号:7626716
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项目类别:
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资助金额:$47.15万
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财政年份:2007
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负责人:Terrance J Kavanagh
-
依托单位:
Modulation of Qdot nanoparticle toxicity by glutathione in GCL transgenic mice
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批准号:7497474
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项目类别:
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资助金额:$45.83万
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财政年份:2007
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负责人:Terrance J Kavanagh
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依托单位:
CORE--Analytical Cytology Laboratory
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批准号:6880487
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项目类别:
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资助金额:$9.66万
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财政年份:2005
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负责人:Terrance J Kavanagh
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依托单位:
CORE--RESEARCH DEVELOPMENT
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批准号:6948125
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项目类别:
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资助金额:$7.08万
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财政年份:2005
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负责人:Terrance J Kavanagh
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依托单位:
CORE--TRAINING
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批准号:6613360
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项目类别:
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资助金额:$22.2万
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财政年份:2002
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负责人:Terrance J Kavanagh
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依托单位:
CORE--TRAINING
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批准号:6577768
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项目类别:
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资助金额:$22.2万
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财政年份:2002
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负责人:Terrance J Kavanagh
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依托单位:
Glutamate-L-cysteine ligase expression and liver injury
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批准号:6785925
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项目类别:
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资助金额:$26.08万
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财政年份:2002
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负责人:Terrance J Kavanagh
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依托单位:
海外基金