Danger Signaling and Spread of Injury after Myocardial Infarction

心肌梗塞后的危险信号和损伤扩散

• 批准号: 9483801
• 负责人: Kevin R King
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9483801
• 关键词: Antiviral Response; Cardiac; Cardiac Myocytes; Cause of Death; Cell Death; Cells; Cessation of life; Congestive Heart Failure; DNA; Development; Dinucleoside Phosphates; Enzyme-Linked Immunosorbent Assay; Exhibits; Fluorescence-Activated Cell Sorting; Gap Junctions; Genes; Goals; Grant; Heart failure; IFNAR1 gene; IRF3 gene; ITGAM gene; Immune; Immune system; Immunologics; Infarction; Inflammation; Injury; Innate Immune Response; Interferon Type I; Interferons; Knock-out; Knockout Mice; Ligands; Mediating; Mediator of activation protein; Molecular; Mus; Myocardial Infarction; PTPRC gene; Pathogenesis; Periodicity; Permeability; Pharmacology; Phase; Play; Research; Risk; Role; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Testing; Therapeutic; Tissues; Vascular blood supply; Ventricular; Ventricular Dysfunction; Western Blotting; Wild Type Mouse; cell type; cytokine; improved; in vivo; inhibitor/antagonist; mortality; novel; pathogen; prevent; response; sensor; transcriptome sequencing; transcriptomics; type I interferon receptor; whole genome

Myocardial infarction (MI) is the leading cause of death in the US. Those that survive, frequently go on to develop ventricular dysfunction and heart failure. While revascularization has dramatically reduced mortality after MI, ongoing efforts to develop post-MI cardioprotective therapies that prevent cardiomyocyte cell death have been unsuccessful. Here, we consider an alternative therapeutic approach, limiting the excessive and maladaptive innate immune response to cell death. When cells die, they release danger signals that overlap with the molecular features that our immune system uses to recognize pathogens. As a result, MI elicits strong innate immune responses. We found that IRF3, a master regulator of the antiviral response plays an unexpected essential role in the pathogenesis of MI. Mice deficient in IRF3 exhibited less inflammation and were strikingly protected from death after MI compared to wild type mice. We hypothesize that multiple cell types in the infarct and borderzone play unique roles in spreading IRF3-dependent signals, promoting immunologic infarct expansion, and increasing the risk of heart failure and death after MI. The scientific aims of this K99/R00 are to 1) identify which danger signaling pathway is responsible for activation of IRF3 after MI, 2) identify which cardiac cell type(s) are responsible for IRF3-mediated injury and death after MI, and 3) to develop pharmacologic inhibitors of IRF3 activation as a novel class of post-MI cardioprotectants. The longterm goal of these studies is to identify cardioprotectants that can be administered post-MI to limit “immunologic infarct expansion” and development of chronic heart failure.

心肌梗死（MI）是美国的主要死亡原因。那些幸存下来的，通常会继续 心室功能障碍和心力衰竭虽然血运重建大大降低了死亡率 心肌梗死后，正在努力开发心肌梗死后心脏保护疗法，防止心肌细胞死亡 都没有成功。在这里，我们考虑一种替代的治疗方法，限制过度和 对细胞死亡的适应不良先天免疫反应。当细胞死亡时，它们会释放出重叠的危险信号 我们的免疫系统用来识别病原体的分子特征。因此，MI非常强大， 先天免疫反应我们发现，IRF 3是抗病毒反应的主要调节因子， 在心肌梗死发病机制中发挥意想不到的重要作用。IRF 3缺陷的小鼠表现出较少的炎症， 与野生型小鼠相比，在MI后显著保护免于死亡。我们假设多细胞 梗死区和边缘区的类型在传播IRF 3依赖性信号，促进 免疫性梗死扩大，并增加心肌梗死后心力衰竭和死亡的风险。科学目标 其中K99/R 00的目的是1）确定哪种危险信号通路负责MI后IRF 3的激活， 2)鉴定哪种心脏细胞类型负责MI后IRF 3介导的损伤和死亡，和3） 开发IRF 3激活的药理学抑制剂作为一类新的MI后心脏保护剂。的长期 这些研究的目的是确定心肌梗死后可以给予的心脏保护剂，以限制“免疫抑制”， 梗塞扩展”和慢性心力衰竭的发展。