PPAR gamma and Nox4 in pulmonary hypertension
PPAR gamma and Nox4 in pulmonary hypertension
批准号:
8207904
负责人:
C MICHAEL HART
金额:
$32.44万
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:
2011-01-01 至 2014-12-31
关键词:
2,4-thiazolidinedioneAffectAnimal ModelAnimalsAttenuatedBindingBlood VesselsCell ProliferationCell WallCellsChronicDataDevelopmentDiseaseEndothelial CellsExperimental ModelsGoalsHumanHypertensionHypoxiaIn VitroKnock-outKnockout MiceLigandsLungMediatingModelingMolecularMorbidity - disease rateMusNADPH OxidaseNuclearNuclear Hormone ReceptorsOxidative StressPPAR gammaPathogenesisPathway interactionsPatientsPlatelet-Derived Growth FactorProductionPublishingPulmonary HypertensionPulmonary artery structureReactive Oxygen SpeciesRegulationRight Ventricular HypertrophyRoleSignal TransductionSmooth MuscleSmooth Muscle MyocytesTherapeutic EffectThiazolidinedionesTransforming Growth Factor betaVascular remodelingWild Type MouseWorkactivating transcription factoreffective therapyhypoxia inducible factor 1in vivoin vivo Modelknockout animalloss of functionmembermortalitymouse modelnovelnovel strategiesoverexpressionpromoterprotective effectpulmonary arterial hypertensionresponsetherapeutic targettreatment strategyvasoconstriction
中文摘要
尽管有现有的治疗方法,但肺动脉高压(PH)会导致显著的发病率和死亡率。
PPARg是PPARg的新靶点
在PH治疗中。越来越多的证据表明,慢性缺氧和其他导致PH的原因是
与NADPH氧化酶NOX4的表达和活性增加有关。NOX4生成
有助于血管收缩、肺血管细胞增殖的活性氧物种,以及
PH发病机制。用噻唑烷二酮配体刺激PPARg可降低其表达和
NOX4的活性和减轻低氧诱导的血管重构,右室肥厚,
和小鼠模型中的肺动脉高压。初步数据证实,NOX4在
特发性肺动脉高压患者的内皮细胞。因此,这
Proposal检验了PPARg激活提供了一种新的减毒策略的假设
低氧诱导的NOX4表达、氧化应激、血管重构和PH。要探索这一点
假设,目标1将研究NOX4在低氧诱导的PH中的作用以及PPARg对其的调节
使用内皮和平滑肌靶向的NOX4基因敲除小鼠。目标2将使用内皮细胞-和
以平滑肌为靶点的PPARg基因敲除或过表达小鼠确定肺血管细胞
对PPARg配体诱导的NOX4和PH改变至关重要的隔室。目标3将
检测PPARg激活抑制NOX4表达的分子机制
肺血管系统。体外研究将使用暴露在低氧环境中的人肺
动脉平滑肌或内皮细胞。这项提案的长期目标是界定
PPARg激活减弱PH并促进新PH发生的机制
心理治疗。
英文摘要
Despite existing therapies, pulmonary hypertension (PH) causes significant morbidity and mortality.
This proposal focuses on peroxisome proliferator-activated receptor gamma (PPARg) as a new target
in PH therapy. Evolving evidence demonstrates that chronic hypoxia and other causes of PH are
associated with increased expression and activity of the NADPH oxidase, Nox4. Nox4 generates
reactive oxygen species that contribute to vasoconstriction, pulmonary vascular cell proliferation, and
PH pathogenesis. Stimulating PPARg with thiazolidinedione ligands reduces the expression and
activity of Nox4 and attenuates hypoxia-induced vascular remodeling, right ventricular hypertrophy,
and pulmonary hypertension in a mouse model. Preliminary data confirm that Nox4 is upregulated in
endothelial cells from patients with idiopathic pulmonary arterial hypertension. Therefore, this
proposal examines the hypothesis that activation of PPARg provides a novel strategy to attenuate
hypoxia-induced Nox4 expression, oxidative stress, vascular remodeling and PH. To explore this
hypothesis, Aim 1 will examine the role of Nox4 in hypoxia-induced PH and its regulation by PPARg
using endothelial- and smooth muscle-targeted Nox4 knockout mice. Aim 2 will use endothelial- and
smooth muscle-targeted PPARg knockout or overexpressing mice to define pulmonary vascular cell
compartments that are critical for PPARg ligand-induced alterations in Nox4 and PH. Aim 3 will
examine the molecular mechanisms by which PPARg activation attenuates Nox4 expression in the
pulmonary vasculature. In vitro studies will be performed using hypoxia-exposed human pulmonary
artery smooth muscle or endothelial cells. The long-term goals of this proposal are to define
mechanisms by which PPARg activation attenuates PH and to facilitate the development of new PH
therapy.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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财政年份:2012
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财政年份:2012
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批准号:8402582
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批准号:8598927
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财政年份:2008
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批准号:7268062
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财政年份:2006
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批准号:7073524
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依托单位:
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批准号:8511776
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依托单位:
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依托单位:
海外基金