Regulation of IL-6-Type Cytokine Cardioprotective Signaling in the Ischemic Heart
缺血性心脏中 IL-6 型细胞因子心脏保护信号的调节
基本信息
- 批准号:7525660
- 负责人:
- 金额:$ 3.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-07-15 至 2008-10-31
- 项目状态:已结题
- 来源:
- 关键词:AdenovirusesAgonistBindingBiochemicalCardiacCardiac MyocytesCardiotonic AgentsCell physiologyChestCoronaryCytokine Inducible SH2-Containing ProteinCytokine SignalingDown-RegulationElementsEmbryonic DevelopmentEndothelial CellsErythropoietinFamilyFunctional disorderGene ExpressionGene TargetingGenesGlutathioneGranulocyte Colony-Stimulating FactorHeartInterleukin-6Ischemic PreconditioningJAK1 geneJanus kinaseKnockout MiceKnowledgeLinkModelingMusMutagenesisMutateMutationMyocardialMyocardial IschemiaMyocardiumNatureNumbersOxidation-ReductionOxygenPathway interactionsPhosphorylationPhysiological reperfusionPlatelet Factor 4ProteinsPublic HealthRecombinant ProteinsRegulationReperfusion TherapyResearchRoleSTAT3 geneSignal TransductionSomatotropinStressTechniquesTestingTherapeuticVascular Endothelial Growth FactorsVascular blood supplybasecardiotrophin 1cytokinedesignheart cellhuman NOS3 proteinin vivoinsightinterestleukemia inhibitory factorloss of functionmutantnovelpreconditioningpreventprogramspromoterprotective effectresearch studytranscription factor
项目摘要
DESCRIPTION (provided by applicant): Activation of JAK-STAT signaling is a common feature of preconditioning and agents that are cardioprotective, including the IL-6-type cytokines. However, mechanisms regulating IL-6 cytokine signaling in the heart are largely unexplored. We propose that the magnitude and protective character of IL-6-type signaling in cardiac muscle is determined by several distinct mechanisms during preconditioning and periods of ischemic stress, including redox-regulation of the JAK kinases and expression of Suppressor of Cytokine Signaling 3 (SOCS3) that terminates IL-6-type cytokine signaling. For the IL-6-family cytokines to be cardioprotective and for preconditioning to occur, we propose that the cellular redox status needs to be maintained and SOCS3 induction in cardiac myocytes must be minimal. Moreover, we hypothesize that while myocardial induction of SOCS3 may prove detrimental to the heart, endothelial SOCS3 is cardioprotective in part by opposing eNOS downregulation. To investigate regulatory mechanisms of cardiac IL-6-family signaling, we propose 3 aims. Aim 1 is to establish the importance of JAK1 redox-sensitivity for ischemic preconditioning. We will assess the impact of glutathione depletion in vivo on IL-6-family cytokine signaling and preconditioning. Mutagenesis and biochemical experiments will be performed to define the mechanism for JAK1 redox- sensitivity. We will also assess if in vivo delivery of a redox-insensitive JAK1 mutant enhances or restores preconditioning protection. Aim 2 will establish the role of the STAT3 - SOCS3 axis in cardiac endothelial cell function. Using cultured mouse coronary endothelial cells from mice carrying a STAT3 S727A mutation, we will test the hypothesis that while binding of STAT3 to promoter elements does not require STAT3 Ser727 phosphorylation, STAT3 transcriptional activity does. We will assess the involvement of STAT3 Ser727 phosphorylation in IL-6 cytokine-induced SOCS3 and vascular endothelial growth factor (VEGF) expression, and eNOS downregulation. We will also test the novel hypothesis that SOCS3 physically interacts with eNOS, and thereby leads to its degradation. Aim 3 is to establish the role of myocardial and endothelial SOCS3 in ischemic preconditioning and will employ a closed-chest mouse myocardial ischemia-reperfusion model. Using cardiomyocyte-targeted SOCS3 knockout mice, we will assess the consequences of myocardial SOCS3 deletion on early and late preconditioning. Mice with targeted loss of SOCS3 in endothelial cells will be used to test the hypothesis that endothelial cell SOCS3 expression is necessary for preconditioning and for preventing endothelial dysfunction. Accomplishment of these aims will vastly extend knowledge of how IL-6 cytokine signaling in the heart is regulated and will have significance for exploiting the therapeutic potential of these cytokines and the phenomenon of preconditioning. PUBLIC HEALTH RELEVANCE: The heart can be protected against damage due to a lack of oxygen by an experimental technique called ischemic preconditioning, which involves briefly shutting off its blood supply. A number of factors are involved in preconditioning, including certain cytokines that activate a particular signaling cascade in heart cells. Our research is focused on understanding how that cascade is turned on and off with the hope that this knowledge could be used therapeutically to prevent ischemic damage to the heart.
描述(由申请人提供):JAK-STAT信号的激活是预适应和具有心脏保护作用的药物的共同特征,包括IL-6型细胞因子。然而,在心脏中调节IL-6细胞因子信号的机制在很大程度上还没有被探索。我们认为,心肌中IL-6型信号的大小和保护特性是由几种不同的机制决定的,包括JAK激酶的氧化还原调节和终止IL-6型细胞因子信号转导的细胞因子信号抑制因子3(SOCS3)的表达。为了使IL-6家族的细胞因子具有心脏保护作用和发生预适应,我们认为需要维持细胞的氧化还原状态,并且对心肌细胞的SOCS3诱导必须是最低限度的。此外,我们假设,尽管心肌SOCS3的诱导可能证明对心脏有害,但内皮SOCS3在一定程度上是通过对抗eNOS下调而起到心脏保护作用的。为了研究心脏IL-6家族信号的调控机制,我们提出了3个目标。目的1是确定JAK1氧化还原敏感性在缺血预适应中的重要性。我们将评估体内谷胱甘肽耗竭对IL-6家族细胞因子信号转导和预适应的影响。将进行突变和生化实验,以确定JAK1氧化还原敏感性的机制。我们还将评估体内传递氧化还原不敏感的JAK1突变体是否增强或恢复预适应保护。目的2确定STAT3-SOCS3轴在心脏内皮细胞功能中的作用。利用培养的携带STAT3 S727A突变的小鼠冠状动脉内皮细胞,我们将检验这样的假设,即虽然STAT3与启动子元件的结合不需要STAT3 Ser727磷酸化,但STAT3的转录活性需要。我们将评估STAT3Ser727磷酸化在IL-6细胞因子诱导的SOCS3和血管内皮生长因子(VEGF)表达以及eNOS下调中的作用。我们还将检验这一新的假设,即SOCS3与eNOS物理相互作用,从而导致其降解。目的3确定心肌和内皮SOCS3在缺血预适应中的作用,并将采用小鼠闭胸心肌缺血再灌注模型。利用以心肌细胞为靶点的SOCS3基因敲除小鼠,我们将评估心肌SOCS3缺失对早期和晚期预适应的影响。内皮细胞中SOCS3靶向缺失的小鼠将被用来检验内皮细胞SOCS3表达对于预适应和预防内皮功能障碍是必要的假设。这些目标的实现将极大地扩展对IL-6细胞因子信号在心脏中的调控方式的认识,并将对挖掘这些细胞因子的治疗潜力和预适应现象具有重要意义。与公共健康相关:通过一种名为缺血预适应的实验技术,可以保护心脏免受缺氧造成的损害,这种技术涉及短暂切断心脏的血液供应。预适应涉及许多因素,包括激活心肌细胞中特定信号级联反应的某些细胞因子。我们的研究重点是了解这一级联反应是如何开启和关闭的,希望这一知识可以用于治疗,以防止心脏缺血性损害。
项目成果
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10.1378/chest.128.4_meetingabstracts.154s - 发表时间:
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George W. Booz的其他文献
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{{ truncateString('George W. Booz', 18)}}的其他基金
Regulation of IL-6-Type Cytokine Cardioprotective Signaling in the Ischemic Heart
缺血性心脏中 IL-6 型细胞因子心脏保护信号的调节
- 批准号:
7838908 - 财政年份:2009
- 资助金额:
$ 3.61万 - 项目类别:
Regulation of IL-6-Type Cytokine Cardioprotective Signaling in the Ischemic Heart
缺血性心脏中 IL-6 型细胞因子心脏保护信号的调节
- 批准号:
7869220 - 财政年份:2008
- 资助金额:
$ 3.61万 - 项目类别:
Regulation of IL-6-Type Cytokine Cardioprotective Signaling in the Ischemic Heart
缺血性心脏中 IL-6 型细胞因子心脏保护信号的调节
- 批准号:
7738162 - 财政年份:2008
- 资助金额:
$ 3.61万 - 项目类别:
Regulation of IL-6-Type Cytokine Cardioprotective Signaling in the Ischemic Heart
缺血性心脏中 IL-6 型细胞因子心脏保护信号的调节
- 批准号:
7658286 - 财政年份:2008
- 资助金额:
$ 3.61万 - 项目类别:
Regulation of IL-6-Type Cytokine Cardioprotective Signaling in the Ischemic Heart
缺血性心脏中 IL-6 型细胞因子心脏保护信号的调节
- 批准号:
8259432 - 财政年份:2008
- 资助金额:
$ 3.61万 - 项目类别:
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