Resolution of inflammation in healing myocardial infarcts

缓解心肌梗塞中的炎症

基本信息

批准号：
8212055
负责人：
Nikolaos G Frangogiannis
金额：
$ 36.98万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
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：
2008-01-15 至 2013-06-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8212055
关键词：
Affect Angiogenesis Inhibitors Animals Area Attenuated Cardiac Cells Characteristics Cicatrix Collaborations Containment Defect Deposition Development Down-Regulation Endothelial Cells Enzymes Equilibrium Event Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Fibrosis Functional disorder Future 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 Investigation Laboratories Lead Left Ventricular Remodeling Letters Leukocytes Matrix Metalloproteinases Mediating Mediator of activation protein Molecular Mus Myocardial Infarction Myocardium Myofibroblast Pathogenesis Pathway interactions Peptides Play Principal Investigator Proteins Proteolysis Protocols documentation Recombinant Proteins Regulation Repression Research Research Proposals Resistance Resolution Role Series Signal Pathway Signal Transduction Suggestion Testing Therapeutic Intervention Thrombospondin 1 Time Tissues Transforming Growth Factor beta Transglutaminases base cardiac repair chemokine crosslink cytokine design experience healing in vivo interstitial leukocyte activation migration overexpression prevent programs promoter recombinant peptide recombinase repaired research study response wound

项目摘要

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肉芽组织形成后抑制炎症反应以及限制纤维化向非梗塞心肌扩张的机制。我们的项目研究了解决梗死后炎症和向纤维组织沉积转变的机制。我们的初步实验表明，血小板反应蛋白 (TSP)-1（一种有效的血管抑制介质和重要的 TGF-2 激活剂）和基质交联酶组织转谷氨酰胺酶 (tTG) 在梗塞边界区选择性诱导，并且 TSP-1 发挥着关键作用在梗塞愈合过程中抑制趋化因子反应和消除炎症浸润中发挥作用。 TSP-1和tTG的选择性定位表明，通过其独特的组成，梗塞边界区可以充当防止肉芽组织形成扩张到非梗塞心肌中的屏障。具体目标 1 将检查 TSP-1 在抑制和遏制梗塞后炎症反应中的作用。检查 TGF-2 信号通路激活和新生血管形成的体内实验，使用从 TSP-1 -/- 和 WT 小鼠中分离的内皮细胞和梗死肌成纤维细胞的体外研究以及注射恢复 TSP-1 分子特定作用的肽将可用于检查 TSP-1 介导效应的机制基础。具体目标2将检验以下假设：tTG可以通过局部激活TGF-β并形成由抗蛋白水解基质组成的“屏障”来防止白细胞迁移，从而保护非梗塞心肌。将使用 tTG -/- 小鼠进行体内研究，并使用来自 WT 和 tTG -/- 小鼠的梗死肌成纤维细胞和内皮细胞进行体外实验。具体目标 3 将探索 TGF-2 通过抑制内皮细胞中趋化因子和细胞因子表达来抑制炎症，以及通过诱导细胞外基质蛋白和改变心脏中 MMP:TIMP 平衡来促进纤维化的独特作用的信号传导途径。成纤维细胞。将使用心肌梗塞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Smad依赖性和Smad非依赖性途径在梗塞后炎症和纤维组织沉积中的重要性。这些研究可能会导致治疗干预措施，旨在通过防止炎症损伤的延长和扩展来优化心脏修复。