Mechanisms and Consequences of Reduced PPAR gamma in Pulmonary Hypertension
肺动脉高压中 PPAR γ 减少的机制和后果
基本信息
- 批准号:8440548
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-10-01 至 2016-09-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdverse effectsAffectAttenuatedBehaviorBindingBlood VesselsCell ProliferationCell WallChronicChronic Obstructive Airway DiseaseCollagenComplexComplicationCongestive Heart FailureDataDevelopmentDiseaseDown-RegulationElectrophoretic Mobility Shift AssayEndothelin-1EventExposure toFunctional disorderGene ExpressionHIV InfectionsHealthcareHumanHypertensionHypoxiaIn VitroInterstitial Lung DiseasesLeadLigandsLower respiratory tract structureLuciferasesLungMeasuresMediator of activation proteinMicroRNAsModelingMorbidity - disease rateMusNADPH OxidaseNF-kappa BNamesNuclear Hormone ReceptorsObstructive Sleep ApneaOutcomePPAR gammaPathogenesisPathway interactionsPatientsPeroxisome Proliferator-Activated ReceptorsPharmaceutical PreparationsPolymerase Chain ReactionPost-Transcriptional RegulationPreventionPublishingPulmonary Heart DiseasePulmonary HypertensionPulmonary artery structurePulmonary vesselsReceptor ActivationRelative (related person)ReporterResearchResearch PersonnelReverse Transcriptase Polymerase Chain ReactionRoleSignal PathwaySmall Interfering RNASmooth Muscle MyocytesStimulusTechniquesTherapeuticTherapeutic EffectThrombospondin 1TimeUntranslated RegionsVascular DiseasesVascular Endothelial Growth Factor ReceptorVascular remodelingVeteransWestern Blottingdosageeffective therapyhypertension treatmentimprovedin vivomortalitynovelnovel strategiesnovel therapeuticsoverexpressionpatient populationperoxisomepreventprogramspromoterpublic health relevancepulmonary arterial hypertensionreceptorvasoconstriction
项目摘要
DESCRIPTION (provided by applicant):
Pulmonary hypertension (PH) is a devastating cardiopulmonary disorder with significant morbidity and mortality that frequently complicates disorders that affect the veteran patient population. Existing PH therapies are expensive and not optimally effective, indicating that novel approaches to PH treatment are urgently needed. This proposal seeks to define new pathways in PH pathogenesis and develop novel strategies for PH therapy. The proposed studies focus on the nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPARg) which has been implicated in PH pathogenesis. Reduced PPARg expression caused PH whereas activation of PPARg with existing medications attenuated PH. Unfortunately, these same PPARg ligands also cause significant side effects. Thus to avoid these adverse effects, this proposal examines mechanisms of PPARg downregulation in PH and ways to prevent it as a new and alternative strategy in PH therapy. The investigators will examine PH in mice caused by exposure to chronic hypoxia ¿ treatment with a vascular endothelial growth factor receptor (VEGF-R) antagonist. Complementary studies will be performed in vitro in human pulmonary artery endothelial or smooth muscle cells (HPAEC or HPASMC) exposed to hypoxia or in HPAEC or HPASMC isolated from control or PH patients. The investigators hypothesize that hypoxia- induced reductions in PPARg in the pulmonary vascular wall promote the expression of downstream mediators that cause vascular cell proliferation, remodeling and PH. Further, it is predicted that preventing or attenuating reductions in PPARg expression and function will reduce proliferative mediator expression and PH. The proposal will address 2 specific aims. The first aim focuses on transcriptional mechanisms that regulate PPARg expression. Aim 1 will determine the role of NF-kB in suppressing PPARg promoter activity. Published and preliminary data demonstrate that NF-kB is activated in PH and by exposure to chronic hypoxia. The expression of PPARg and downstream PPARg-regulated proliferative mediators (including NADPH oxidase 4, endothelin-1, and thrombospondin-1) will be measured in the proposed models using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Vascular cell proliferation, vascular remodeling, and PH will be determined with techniques published by the investigative team. Activation of NF-kB will be determined by electrophoretic mobility shift assays. siRNA will be administered to inhibit NF-kB to determine its role in reduced PPARg expression and in the increased expression of proliferative mediators that cause PH. Aim 2 will focus on the post-transcriptional regulation of PPARg by microRNA-27 (miR-27). Levels of miR-27 will be measured in the models employed in Aim 1 using qRT-PCR, and its role in PH pathobiology will be established using miR-27 antagonists or overexpression. Binding of miR-27 to the PPARg 3'-UTR will be confirmed using luciferase reporter constructs. Intranasal delivery of anti-miR-27 to the lower respiratory tract will be used in vivo to determine
if preventing increases in miR-27 can avert reductions in PPARg and attenuate downstream increases in proliferative mediators. The proposed studies will clarify pathogenic mechanisms in PH and define the relative contributions of transcriptional and post-transcriptional pathways to reductions in PPARg. The outcomes will determine if strategies to prevent reductions in pulmonary vascular PPARg expression can provide a novel approach to PH therapy. The proposed strategies might also enhance the therapeutic effects of existing PPARg ligands thereby permitting reductions in dosage and associated side effects. The results of this proposal can thereby define novel and effective therapeutic strategies to regulate programs of gene expression involved in PH pathogenesis.
描述(由申请人提供):
肺动脉高压(PH)是一种具有显著发病率和死亡率的破坏性心肺疾病,经常使影响退伍军人患者群体的疾病复杂化。现有的PH疗法昂贵且效果不佳,这表明迫切需要PH治疗的新方法。 该提案旨在确定PH发病机制的新途径,并开发PH治疗的新策略。 拟议的研究集中在核激素受体,过氧化物酶体增殖物激活受体γ(PPARg),这已牵连在PH的发病机制。PPARg表达减少导致PH,而现有药物对PPARg的激活减弱PH。不幸的是,这些相同的PPARg配体也引起显著的副作用。因此,为了避免这些不良反应,本提案研究了PH中PPARg下调的机制以及预防其作为PH治疗中新的替代策略的方法。研究人员将检查暴露于慢性缺氧的小鼠中的PH,该小鼠接受血管内皮生长因子受体(VEGF-R)拮抗剂治疗。将在暴露于缺氧的人肺动脉内皮或平滑肌细胞(HPAEC或HPASMC)或从对照或PH患者分离的HPAEC或HPASMC中进行体外补充研究。研究者推测,缺氧诱导的肺血管壁中PPARg的减少促进了下游介质的表达,这些介质导致血管细胞增殖、重塑和PH。此外,预测防止或减弱PPARg表达和功能的减少将减少增殖介质的表达和PH。该提案将解决2个具体目标。第一个目标集中在调节PPARg表达的转录机制。目的1确定NF-κ B在抑制PPARg启动子活性中的作用。已发表的和初步的数据表明,NF-κ B在PH和暴露于慢性缺氧中被激活。将使用定量实时聚合酶链反应(qRT-PCR)和蛋白质印迹法在拟定模型中测量PPARg和下游PPARg调节的增殖介质(包括NADPH氧化酶4、内皮素-1和血小板反应蛋白-1)的表达。血管细胞增殖、血管重塑和PH将采用研究小组发表的技术进行测定。将通过电泳迁移率变动试验测定NF-κ B的活化。将施用siRNA来抑制NF-kB以确定其在减少PPARg表达和增加引起PH的增殖介质的表达中的作用。Aim 2将集中于微小RNA-27(miR-27)对PPARg的转录后调节。将使用qRT-PCR在目标1中采用的模型中测量miR-27的水平,并将使用miR-27拮抗剂或过表达确定其在PH病理生物学中的作用。将使用荧光素酶报告基因构建体确认miR-27与PPARg 3 '-UTR的结合。将在体内使用鼻内递送抗miR-27至下呼吸道以确定
如果阻止miR-27的增加可以避免PPARg的减少并减弱下游增殖介质的增加。拟议的研究将阐明PH的致病机制,并确定转录和转录后途径对PPARg减少的相对贡献。这些结果将确定预防肺血管PPARg表达减少的策略是否可以为PH治疗提供一种新方法。所提出的策略还可以增强现有PPARg配体的治疗效果,从而允许减少剂量和相关副作用。因此,该建议的结果可以定义新的和有效的治疗策略,以调节PH发病机制中涉及的基因表达程序。
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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C MICHAEL HART其他文献
C MICHAEL HART的其他文献
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{{ truncateString('C MICHAEL HART', 18)}}的其他基金
Mitophagy in pulmonary hypertension: Novel roles of PTEN-Induced Kinase-1 in the pathobiology of pulmonary artery smooth muscle cell proliferation and mitochondrial dysfunction
肺动脉高压中的线粒体自噬:PTEN 诱导的激酶 1 在肺动脉平滑肌细胞增殖和线粒体功能障碍病理学中的新作用
- 批准号:
9974277 - 财政年份:2019
- 资助金额:
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Mitophagy in pulmonary hypertension: Novel roles of PTEN-Induced Kinase-1 in the pathobiology of pulmonary artery smooth muscle cell proliferation and mitochondrial dysfunction
肺动脉高压中的线粒体自噬:PTEN 诱导的激酶 1 在肺动脉平滑肌细胞增殖和线粒体功能障碍病理学中的新作用
- 批准号:
10266041 - 财政年份:2019
- 资助金额:
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Mitophagy in pulmonary hypertension: Novel roles of PTEN-Induced Kinase-1 in the pathobiology of pulmonary artery smooth muscle cell proliferation and mitochondrial dysfunction
肺动脉高压中的线粒体自噬:PTEN 诱导的激酶 1 在肺动脉平滑肌细胞增殖和线粒体功能障碍病理学中的新作用
- 批准号:
10881631 - 财政年份:2019
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Mechanisms and Consequences of Reduced PPAR gamma in Pulmonary Hypertension
肺动脉高压中 PPAR γ 减少的机制和后果
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8598800 - 财政年份:2012
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PPAR gamma and Nox4 in pulmonary hypertension
PPAR γ 和 Nox4 在肺动脉高压中的作用
- 批准号:
8402582 - 财政年份:2011
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PPAR gamma and Nox4 in pulmonary hypertension
PPAR γ 和 Nox4 在肺动脉高压中的作用
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8963181 - 财政年份:2011
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PPAR gamma and Nox4 in pulmonary hypertension
PPAR γ 和 Nox4 在肺动脉高压中的作用
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8207904 - 财政年份:2011
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PPAR gamma and Nox4 in pulmonary hypertension
PPAR γ 和 Nox4 在肺动脉高压中的作用
- 批准号:
8598927 - 财政年份:2011
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PPAR gamma and Nox4 in pulmonary hypertension
PPAR γ 和 Nox4 在肺动脉高压中的作用
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8039688 - 财政年份:2011
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PPAR gamma regulates vascular endothelial reactive species production in diabetes
PPAR γ 调节糖尿病血管内皮活性物质的产生
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