Resolution of Inflammation in healing Myocardial Infarcts

缓解心肌梗塞中的炎症

基本信息

批准号：
8682984
负责人：
Nikolaos G Frangogiannis
金额：
$ 40.92万
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 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8682984
关键词：
Acute Affect Area Biological Biology Cardiac Cardiac Myocytes Cells Cicatrix Complement Containment Defect Development Down-Regulation Extracellular Matrix Family Fibroblasts Functional disorder Funding Healed Heart failure Immune Immune response In Vitro Infarction Infiltration Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Injury Interleukin 2 Receptor Interleukin Receptor Interleukin-1 Interleukin-1 Receptors Interleukins Knockout Mice Laboratories Leukocytes MAP Kinase Gene Mediating Molecular Myocardial Infarction Myocardium Necrosis Pathogenesis Pathway interactions Phenotype Phosphotransferases Play Process Proteins Reaction Regulation Repression Resolution Role Signal Pathway Signal Transduction System Testing Time Tissues Toll-Like Receptor 1 Up-Regulation base cell type chemokine cytokine gain of function healing in vivo insight macrophage member monocyte novel prevent protective effect public health relevance receptor repaired research study response therapeutic target tissue repair wound

项目摘要

DESCRIPTION (provided by applicant): Myocardial infarction triggers an intense inflammatory reaction that serves to clear the infarct from dead cells and matrix debris. Optimal repair of the infarcted myocardium requires timely resolution of inflammation and activation of endogenous inhibitory pathways that restrain the inflammatory response protecting the infarcted heart from excessive matrix degradation and adverse remodeling. Defects in the STOP signals responsible for containment and resolution of post-infarction inflammation may result in accentuated chamber dilation and contribute to the development of heart failure. Toll-Like Receptor (TLR)/Interleukin (IL)-1 signaling pathways are critical for initiation of the inflammator cascade following tissue injury, but need to be tightly regulated in order to prevent an overactive immunoinflammatory response. We hypothesized that activation of endogenous inhibitory signals is necessary for negative regulation of the TLR/IL-1 response following myocardial infarction, in order to prevent uncontrolled inflammation and to limit dilative remodeling. We will explore two novel pathways responsible for inhibition of the innate immune response in the infarcted myocardium: 1) We have identified Interleukin Receptor Associated Kinase (IRAK)-M, a member of the IRAK-M family that lacks kinase activity, as a key intracellular signal that is upregulated following myocardial infarction and protects the infarcted heart from adverse remodeling restraining inflammation and preventing excessive matrix degradation. IRAK-M expression in infarct macrophages inhibits their inflammatory activity. Our experiments suggest that IRAK-M upregulation in cardiac fibroblasts may limit their matrix-degrading capacity without affecting their inflammatory potential; these effects may be mediated through novel biological interactions between IRAK-M and the TGF-¿ system. 2) We suggest that dynamic, cell type-specific changes in expression of the signaling type 1 IL-1 receptor (IL-1R1) and of the decoy type 2 receptor (IL-1R2) may play a crucial role in regulation of the inflammatory and reparative response following infarction. Early IL-1R1 upregulation in monocytes/macrophages and in cardiac fibroblasts may induce inflammatory actions, whereas late downregulation of IL-1R1 and induction of the decoy receptor IL-1R2 may serve as a molecular sink terminating IL-1 signaling in the in infarcted myocardium. These concepts will be explored in three specific aims: Specific aim 1: to study the role of endogenous IRAK-M upregulation as a protective mechanism that restrains TLR/IL-1-driven inflammation, preventing hyperactive monocyte/macrophage responses and protecting from adverse post- infarction remodeling. Specific aim 2: to study the role of IRAK-M in modulating fibroblast phenotype and in regulating matrix remodeling following myocardial infarction and to dissect the pathways responsible for IRAK-M actions in cardiac fibroblasts. Specific aim 3: To study the role of cell-type specific changes in expression of signaling and decoy IL-1Rs in regulation of inflammation and repair following myocardial infarction. Our studies will provide new insights into the pathogenesis of adverse remodeling and heart failure following myocardial infarction and may identify new promising therapeutic targets. In addition, the novel effects of IRAK-M on fibroblast function and its potential interactions with the TGF- ¿ pathway have important implications in the biology of tissue inflammation and repair.

描述（由申请人提供）：心肌梗塞会引发强烈的炎症反应，从而清除梗塞处的死亡细胞和基质碎片。梗塞心肌的最佳修复需要及时解决炎症并激活抑制炎症反应的内源性抑制途径，从而保护炎症反应。因基质过度降解和不良重塑而导致的梗塞心脏，负责抑制和解决梗塞后炎症的 STOP 信号缺陷可能会导致病情加重。心室扩张并导致心力衰竭的发生。Toll 样受体 (TLR)/白细胞介素 (IL)-1 信号通路对于组织损伤后炎症级联反应的启动至关重要，但需要严格调节以防止发生炎症反应。过度活跃我们发现内源性抑制信号的激活对于心肌梗死后 TLR/IL-1 反应的负调节是必要的，以防止不受控制的炎症并限制扩张性重塑。探索两种负责抑制梗塞心肌先天免疫反应的新途径：1) 我们已经确定白细胞介素受体相关激酶 (IRAK)-M（缺乏激酶活性的 IRAK-M 家族成员）作为关键的细胞内信号心肌梗塞后上调，保护梗塞心脏免受重塑，抑制炎症并防止梗塞巨噬细胞中的过度基质降解。我们的实验表明，心脏成纤维细胞中 IRAK-M 的上调可能会限制其基质降解能力，而不影响其炎症潜力；这些作用可能是通过 IRAK-M 和 TGF-¿ 2) 我们认为，1 型 IL-1 受体 (IL-1R1) 和 2 型诱饵受体 (IL-1R2) 表达的动态、细胞类型特异性变化可能在调节中发挥关键作用。梗塞后的早期 IL-1R1 在单核细胞/巨噬细胞和心脏成纤维细胞中的上调可能诱导炎症反应，而晚期 IL-1R1 的下调和诱导。诱饵受体 IL-1R2 可能作为终止梗塞心肌中 IL-1 信号转导的分子汇，将在三个具体目标中探讨这些概念：具体目标 1：研究内源性 IRAK-M 上调作为保护机制的作用。抑制 TLR/IL-1 驱动的炎症，防止过度活跃的单核细胞/巨噬细胞反应并防止不良的梗死后重塑。具体目标 2：研究其作用。 IRAK-M 在调节成纤维细胞表型和调节心肌梗死后的基质重塑中的作用，并剖析负责 IRAK-M 在心脏成纤维细胞中作用的途径。具体目标 3：研究细胞类型特异性变化在信号传导和诱饵表达中的作用。 IL-1R 在心肌梗死后炎症和修复的调节中的作用我们的研究将为心肌梗死后不良重塑和心力衰竭的发病机制提供新的见解。此外，IRAK-M 对成纤维细胞功能的新作用及其与 TGF-¿ 的潜在相互作用。通路对组织炎症和修复的生物学具有重要意义。