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: 9107909
• 负责人: Kevin R King
• 金额: $ 17.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107909
• 关键词: Adaptor Signaling Protein; Alcohols; Antiviral Response; Attention; Biological Assay; Biometry; Cardiac; Cardiac Myocytes; Cardiology; Cause of Death; Cell Death; Cells; Cessation of life; Clinical; Communication; Congestive Heart Failure; Custom; Cytoplasm; Data; Development; Diet; Drug Delivery Systems; Engineering; Enzyme-Linked Immunosorbent Assay; Exhibits; Flow Cytometry; Gap Junctions; Gene Expression; Genetic; Goals; Grant; Heart; Heart failure; IRF3 gene; Immune response; Immune system; Immunohistochemistry; Immunologics; Immunology; Immunosuppression; In Vitro; Infarction; Infection; Inflammation; Inflammatory; Injury; Interferons; Knock-out; Knockout Mice; Laboratories; Leukocytes; Liver; Magnetic Resonance Imaging; Mediating; Mediator of activation protein; Mentors; Molecular; Mus; Myocardial Infarction; Natural Immunity; Nucleotides; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Phenocopy; Phenotype; Phosphotransferases; Physicians; Play; Production; Recruitment Activity; Reporter; Research; Risk; Role; Scientist; Signal Pathway; Signal Transduction; Sterility; Structure; System; TBK1 gene; Testing; Therapeutic; Tissues; Training; Vascular blood supply; Ventricular Dysfunction; Wild Type Mouse; amlexanox; base; cell type; chemokine; cytokine; in vivo; inhibitor/antagonist; injured; intravital microscopy; macrophage; molecular imaging; mortality; mouse model; multidisciplinary; nanoparticle; novel; pathogen; prevent; response; responsible research conduct; sensor; therapeutic development

 DESCRIPTION (provided by applicant): 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 used by our immune system 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 significantly less inflammation and were strikingly protected from death after MI compared to wild type mice. We hypothesize that cardiomyocytes and cardiac resident macrophage in the infarct 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 long-term 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. The applicant is a physician-scientist trained in engineering, innate immunity, and clinical cardiology. This grant will facilitate his transition to investigative independence through 1) structured training in advanced immunology, molecular imaging, biostatistics, responsible conduct of research, and laboratory management; and 2) guidance from a multidisciplinary team of mentors and advisors comprised of experts in clinical cardiology, cardiac immunology, innate immunity, molecular imaging, therapeutics development, and drug delivery.

 描述（由申请人提供）：心肌梗塞 (MI) 是美国的主要原因。那些存活下来的人经常会出现心室功能障碍和心力衰竭。虽然血运重建极大地降低了心肌梗死后的死亡率，但持续的努力 开发预防心肌细胞死亡的心肌梗死后心脏保护疗法尚未成功。在这里，我们考虑一种替代治疗方法，限制对细胞死亡的过度和适应不良的先天免疫反应。当细胞死亡时，它们会释放出危险信号，这些信号与我们的免疫系统识别病原体所使用的分子特征重叠。因此，心肌梗死会引发强烈的先天免疫反应。我们发现 IRF3 作为抗病毒反应的主要调节因子，在 MI 的发病机制中发挥着意想不到的重要作用。与野生型小鼠相比，IRF3 缺陷的小鼠表现出明显较少的炎症，并且在 MI 后显着防止死亡。我们假设梗塞边界区的心肌细胞和心脏驻留巨噬细胞在传播 IRF3 依赖性信号、促进免疫性梗塞扩张以及增加 MI 后心力衰竭和死亡的风险方面发挥独特的作用。该 K99/R00 的科学目标是 1) 确定哪种危险信号通路负责 MI 后 IRF3 的激活，2) 确定哪些心肌细胞类型负责 IRF3 介导的 MI 后损伤和死亡，以及 3) 开发 IRF3 激活的药理学抑制剂作为一类新型 MI 后心脏保护剂。这些研究的长期目标是确定可以在心肌梗塞后使用的心脏保护剂，以限制“免疫性梗塞扩张”和慢性心力衰竭的发展。申请人是一位接受过工程、先天免疫和临床心脏病学培训的医师兼科学家。这笔赠款将通过以下方式促进他向独立研究的过渡：1）高级免疫学、分子成像、生物统计学、负责任的研究行为和实验室管理方面的结构化培训； 2) 来自多学科导师和顾问团队的指导，该团队由临床心脏病学、心脏免疫学、先天免疫、分子成像、治疗开发和药物输送方面的专家组成。