Resolution of inflammation in healing myocardial infarcts

缓解心肌梗塞中的炎症

• 批准号: 7556351
• 负责人: Nikolaos G Frangogiannis
• 金额: $ 34.54万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7556351
• 关键词: Affect; Angiogenesis Inhibitors; Area; Attenuated; Cardiac; Cells; Characteristics; Cicatrix; Containment; Defect; Deposition; Development; Down-Regulation; Endothelial Cells; Enzymes; Equilibrium; Event; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Functional disorder; Gene Expression; Genes; Goals; Granulation Tissue; Healed; Heart; In Vitro; Infarction; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Injection of therapeutic agent; Injury; Lead; Left Ventricular Remodeling; Leukocytes; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Molecular; Mus; Myocardial Infarction; Myocardium; Myofibroblast; Pathogenesis; Pathway interactions; Peptides; Play; Proteolysis; Protocols documentation; Recombinant Proteins; Regulation; Repression; Resistance; Resolution; Role; Series; Signal Pathway; Signal Transduction; Testing; Therapeutic Intervention; Thrombospondin 1; Time; Tissues; Transforming Growth Factor beta; Transglutaminases; base; chemokine; crosslink; cytokine; healing; in vivo; interstitial; leukocyte activation; migration; prevent; repaired; research study; response; wound

DESCRIPTION (provided by applicant): Effective repair of the infarcted heart depends on mechanisms that suppress the inflammatory response after granulation tissue formation has occurred, and that limit expansion of fibrosis to the non-infarcted myocardium. Our project examines the mechanisms responsible for resolution of post-infarction inflammation and transition to fibrous tissue deposition. Our preliminary experiments suggest that Thrombospondin (TSP)-1, a potent angiostatic mediator and crucial TGF-2 activator, and the matrix crosslinking enzyme tissue transglutaminase (tTG), are selectively induced in the infarct border zone and that TSP-1 plays a key role in suppression of the chemokine response and resolution of the inflammatory infiltrate in healing infarcts. The selective localization of TSP-1 and tTG suggests that, through its unique composition, the infarct border zone may serve as a barrier preventing expansion of granulation tissue formation into the non- infarcted myocardium. Specific aim 1 will examine the role of TSP-1 in suppression and containment of the post-infarction inflammatory response. In vivo experiments examining activation of TGF-2 signaling pathways and neovessel formation, in vitro studies using endothelial cells and infarct myofibroblasts isolated from TSP-1 -/- and WT mice and injections of peptides that restore specific actions of the TSP-1 molecule will be used to examine the mechanistic basis of the TSP-1-mediated effects. Specific aim 2 will test the hypothesis that tTG may protect the non-infarcted myocardium by locally activating TGF- beta and by forming a "barrier" composed of proteolysis-resistant matrix, preventing leukocyte migration. In vivo studies using tTG -/- mice and in vitro experiments using infarct myofibroblasts and endothelial cells from WT and tTG -/- mice will be performed. Specific aim 3 will explore the signaling pathways responsible for the distinct effects of TGF-2 in suppressing inflammation by repressing chemokine and cytokine expression in endothelial cells, and in promoting fibrosis, by inducing extracellular matrix proteins and by altering the MMP:TIMP balance in cardiac fibroblasts. The importance of Smad- dependent and Smad-independent pathways in post-infarction inflammation and fibrous tissue deposition will be examined using myocardial infarction experiments and in vitro studies on isolated endothelial cells and fibroblasts. These studies may lead to therapeutic interventions aimed at optimizing cardiac repair by preventing prolongation and extension of the inflammatory injury.

描述（由申请人提供）：梗塞心脏的有效修复取决于发生肉芽组织形成后抑制炎症反应的机制，并且将纤维化限制为非芳香心肌的膨胀。我们的项目研究了负责解决炎症后炎症和过渡到纤维组织沉积的机制。我们的初步实验表明，血小板素（TSP）-1，有效的血管抑制剂和关键的TGF-2激活剂，以及基质交联酶组织（TTG）的基质交联酶（TTG）在基数边界和该抑制作用中的键入性中的键入性和重点均在促进性的作用中选择性地诱导，并且在抑制中均具有抑制作用，并且在抑制中的抑制作用均具有疗法的疗法，该疗法的疗法是在疗法中的疗法，该疗法的疗法是在疗法中的疗法。梗塞。 TSP-1和TTG的选择性定位表明，通过其独特的组成，梗塞边界区可以用作屏障，以防止肉芽组织形成扩展到非梗塞的心肌中。具体目标1将检查TSP-1在抑制和遏制炎症后炎症反应中的作用。研究了使用内皮细胞的TGF-2信号传导途径和新无动壳的激活的体内实验，并从TSP-1 - / - 和WT小鼠中分离出的内皮细胞和梗死的肌纤维细胞进行体外研究，并注入了TSP-1分子的特定作用的肽的注射，用于恢复TSP-1的特定作用，以恢复TSP-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-MIDIEDS-1-MIDIEDS-1 MIDIDED效果。具体目标2将检验以下假设：TTG可以通过局部激活TGF-beta并形成由抗蛋白水解抗性基质组成的“屏障”，以防止白细胞迁移来保护非芳香的心肌。使用TTG - / - 小鼠以及使用WT和TTG - / - 小鼠的梗死成肌纤维细胞和内皮细胞的体内研究。具体目标3将探索负责TGF-2在抑制内皮细胞中趋化因子和细胞因子表达以及促进纤维化中抑制炎症的明显影响的信号传导途径，并通过诱导细胞外基质蛋白和MMP来改变MMP：TIMP在心脏纤维中平衡。将使用心肌梗死实验和对分离的内皮细胞和成纤维细胞的体外研究来检查依赖性和SMAD非依赖性途径在炎症后炎症和纤维组织沉积中的重要性。这些研究可能导致治疗性干预措施，旨在通过防止炎症损伤的延长和扩展来优化心脏修复。