Ventricular Remodeling in the Adapted Heart
适应心脏的心室重塑
基本信息
- 批准号:8027761
- 负责人:
- 金额:$ 40.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-08-01 至 2013-02-28
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAddressAdenovirusesAffinityAngiogenesis InhibitorsAnnexinsAntibodiesApoptosisApoptoticAreaAttentionBCL-2 ProteinBindingBiological AssayBiological ProcessBlood VesselsBlood capillariesBlood flowCardiacCardiac MyocytesCardiovascular systemCell CommunicationCell SurvivalCell physiologyCellsCessation of lifeChronicClinicalCollagenColony-Stimulating FactorsComplexControl GroupsCoronaryCoronary arteryDNA BindingDNA Microarray ChipDataDepositionDevelopmentDiseaseDown-RegulationDrug or chemical Tissue DistributionEchocardiographyEmbryoEndothelial CellsEndotheliumEngineeringEpidermal Growth FactorEpiregulinEventFailureFamilyFundingFutureGelshift AnalysisGene ChipsGene ExpressionGene TargetingGenesGeneticGoalsGrantGrowth FactorHealthHeartHeat shock proteinsHourHumanHypoxiaIkappaB kinaseImageImmunohistochemistryIn VitroInfarctionInformation NetworksInjuryInvestigationIschemiaIschemic PreconditioningKidneyKnock-outKnockout MiceLeadLigandsLungMacrophage Colony-Stimulating FactorMalignant NeoplasmsMeasuresMediatingMedicalMembraneMicroarray AnalysisMitogensModelingMolecularMolecular BiologyMolecular ProfilingMusMuscle CellsMyocardialMyocardial InfarctionMyocardial IschemiaMyocardiumNecrosisOncogenesPathway interactionsPatientsPatternPhosphorylationPhosphotransferasesPhysiologicalPhysiologyPlacental Growth FactorPlayProcessProteinsProto-Oncogene Proteins c-aktProtocols documentationPublishingQuality of lifeRNA InterferenceRattusReceptor Protein-Tyrosine KinasesRegulationResearchRoleSP1 geneSRC geneSTAT3 geneSignal TransductionSmall Interfering RNAStaining methodStainsStimulusStructure of parenchyma of lungSystemSystems DevelopmentTNFRSF5 geneTechniquesTestingTherapeuticTherapeutic InterventionTimeTransfectionTranslatingVascular Endothelial Growth Factor ReceptorVascular Endothelial Growth Factor Receptor-1Vascular Endothelial Growth Factor Receptor-2Vascular Endothelial Growth FactorsVascular EndotheliumVascular PermeabilitiesVentricular FunctionVentricular RemodelingWestern BlottingWorkangiogenesiscapillarycytokinedensitydesigngene repressiongenetic technologyimprovedin vivointerdisciplinary approachinterestmembermouse modelneovascularizationnovelnovel therapeuticspreconditioningprotein expressionreceptorrelease of sequestered calcium ion into cytoplasmrepairedresearch studyresponsesmall hairpin RNAsurvivintherapeutic targettranscription factortreatment strategyvasculogenesis
项目摘要
DESCRIPTION (provided by applicant): The central role of vascular endothelial growth factor (VEGF) in angiogenesis health and disease makes it attractive both as a therapeutic target for anti-angiogenic drugs in pathological conditions such as cancer and as a pro-angiogenic cytokine for the treatment of ischemic heart disease. VEGF modulates the complex process of angiogenesis and other various aspects of endothelial cell function through either of its two tyrosine kinase receptors, VEGFR1/Flt-1 or VEGFR2/Flk1/KDR via its target protein MK2. In the present proposal we will use Flk-1 , Flt-1 and MK2-/- (MAPKAPKinase2) knockout mice in an attempt to address an important clinical issue to identify potential downstream candidates of VEGF signaling through its receptors that trigger cardioprotective signal during ischemic preconditioning (IP). By Affymetrix gene chip analysis we demonstrated for the first time down regulation of genes (Pellino-1 or Peli-1, Epiregulin and NF?B) after ischemic insult to the Flk-1 mice compared to WT. Studies have identified candidates of the Pellino family as a novel upstream regulator in mediating activation of MAPKAP kinase pathway. PELLINO (Peli) and EPIREGULIN (Ereg) are the newly described molecules downstream of VEGF signaling which might play significant role in myocardial angiogenesis leading to the inhibition of ventricular remodeling. Ereg has angiogenic potential, which may contribute to de novo development of vessels by vasculogenesis or angiogenesis in ischemic/infarcted myocardium. Our long-term goal of this project is to understand the mechanism of VEGF signaling in the ischemic myocardium through newly described molecules Peli-1 and Ereg that we have explored in ischemic myocardium very recently. These are the molecules that may be involved in triggering PI3Kinase/MK2/NF?B pathway involved in angiogenesis. Specific Aim I will determine the involvement of Peli-1, 2 and 3 in IP mediated angiogenesis, Aim II will determine the involvement of MK2 and NF?B in Pellino mediated angiogenesis, Aim III will study the involvement of Ereg in VEGF/PI3-kinase/MK2/NF?B mediated angiogenesis, Aim IV will determine the role and involvement of NF?B in VEGF/Pellino/epiregulin/MK2 mediated myocardial angiogenesis. Genetically engineered NF?B knockout (KO) mice will be used to identify VEGF mediated signaling which may be through NF?B, one of the final target genes related to myocardial angiogenesis. This study will adapt multidisciplinary approach that will consist of various techniques such as modern molecular biology, imaging, gene targeting, siRNA technique and physiology. Collectively, the proposal will contribute to our understanding of the molecular mechanism of VEGF induced angiogenesis and in future may provide novel therapeutic treatment strategies against ischemic heart disease. PUBLIC HEALTH RELEVANCE: To understand VEGF signaling mechanism is a promising medical development in the treatment of ischemia that will likely improve the quality of life in patients who have severe ischemic heart disease.
描述(由申请人提供):血管内皮生长因子(VEGF)在血管生成健康和疾病中的中心作用使其作为病理条件如癌症中抗血管生成药物的治疗靶点和作为治疗缺血性心脏病的促血管生成细胞因子具有吸引力。VEGF通过其两种酪氨酸激酶受体(VEGFR 1/Flt-1或VEGFR 2/Flk 1/KDR)中的任一种经由其靶蛋白MK 2调节血管生成的复杂过程和内皮细胞功能的其他各个方面。在本提案中,我们将使用Flk-1,Flt-1和MK 2-/-(MAPKAP激酶2)基因敲除小鼠,试图解决一个重要的临床问题,以确定潜在的下游候选人的VEGF信号通过其受体,触发心脏保护信号在缺血预处理(IP)。通过Affyssin基因芯片分析,我们首次证明了下调基因(Pellino-1或Peli-1,Epiregulin和NF?B)与WT相比,Flk-1小鼠缺血损伤后。研究已经确定Pellino家族的候选者作为介导MAPKAP激酶途径活化的新型上游调节剂。PELLINO(Peli)和EPIREGULIN(Ereg)是新近发现的VEGF信号下游分子,可能在心肌血管生成中发挥重要作用,从而抑制心室重构。Ereg具有血管生成潜力,可能通过缺血/梗死心肌中的血管生成或血管生成促进血管的新生。本项目的长期目标是通过我们最近在缺血心肌中探索的新描述的分子Peli-1和Ereg来了解缺血心肌中VEGF信号传导的机制。这些分子可能参与触发PI 3激酶/MK2/NF?B途径参与血管生成。具体目标我将确定参与Peli-1,2和3在IP介导的血管生成,目的II将确定参与MK 2和NF?B在Pellino介导的血管生成中的作用,目的III将研究Ereg在VEGF/PI 3-kinase/MK2/NF?B介导的血管生成,目的四将确定NF?B在VEGF/Pellino/epiregulin/MK 2介导的心肌血管生成中的作用基因工程NF?B基因敲除(KO)小鼠将用于鉴定VEGF介导的信号传导,其可能通过NF?B,心肌血管生成相关的最终靶基因之一。本研究将采用多学科方法,包括现代分子生物学,成像,基因打靶,siRNA技术和生理学等各种技术。总的来说,该建议将有助于我们了解VEGF诱导血管生成的分子机制,并在未来可能提供新的治疗缺血性心脏病的治疗策略。公共卫生关系:了解血管内皮生长因子的信号传导机制是治疗缺血的一个有前途的医学发展,可能会改善患有严重缺血性心脏病的患者的生活质量。
项目成果
期刊论文数量(0)
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NILANJANA MAULIK其他文献
NILANJANA MAULIK的其他文献
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{{ truncateString('NILANJANA MAULIK', 18)}}的其他基金
Mechanism of Myocardial Angiogenesis in Transgenic/Knockout Animals
转基因/基因敲除动物心肌血管生成机制
- 批准号:
7244441 - 财政年份:2006
- 资助金额:
$ 40.05万 - 项目类别:
Mechanism of Myocardial Angiogenesis in Transgenic/Knockout Animals
转基因/基因敲除动物心肌血管生成机制
- 批准号:
7629142 - 财政年份:2006
- 资助金额:
$ 40.05万 - 项目类别:
Mechanism of Myocardial Angiogenesis in Transgenic/Knockout Animals
转基因/基因敲除动物心肌血管生成机制
- 批准号:
7433127 - 财政年份:2006
- 资助金额:
$ 40.05万 - 项目类别:
Mechanism of Myocardial Angiogenesis in Transgenic/Knockout Animals
转基因/基因敲除动物心肌血管生成机制
- 批准号:
7848062 - 财政年份:2006
- 资助金额:
$ 40.05万 - 项目类别:
Mechanism of Myocardial Angiogenesis in Transgenic/Knockout Animals
转基因/基因敲除动物心肌血管生成机制
- 批准号:
7138758 - 财政年份:2006
- 资助金额:
$ 40.05万 - 项目类别:
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