Danger Signaling and Spread of Injury after Myocardial Infarction

 描述(由申请人提供)：心肌梗死(MI)是美国主要的死亡原因。那些存活下来的人，经常会发展为心功能不全和心力衰竭。虽然血运重建显著降低了心肌梗死后的死亡率，但正在进行的努力 开发预防心肌细胞死亡的心肌梗死后心肌保护疗法一直未获成功。在这里，我们考虑另一种治疗方法，限制细胞死亡的过度和不适应的先天免疫反应。当细胞死亡时，它们释放的危险信号与我们的免疫系统用来识别病原体的分子特征重叠。因此，心肌梗死会引起强烈的先天免疫反应。我们发现，IRF3是抗病毒反应的主要调节者，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基因缺陷的小鼠表现出显著较少的炎症反应，并显著避免了MI后的死亡。我们假设心肌梗死交界区的心肌细胞和心脏驻留巨噬细胞在传播IRF3依赖的信号、促进免疫性心肌梗死扩大、增加心力衰竭和心梗后死亡的风险方面发挥着独特的作用。K99/R00的科学目的是：1)确定心肌梗死后IRF3激活的危险信号通路；2)确定心肌梗死后IRF3介导的损伤和死亡由哪种心肌细胞类型(S)负责；3)开发IRF3激活的药物抑制剂，作为一类新的MI后心脏保护剂。这些研究的长期目标是确定心肌梗死后可以使用的心脏保护剂，以限制“免疫性梗塞扩大”和慢性心力衰竭的发展。申请者是一位在工程学、先天免疫学和临床心脏病学方面受过训练的内科科学家。这笔赠款将通过1)高级免疫学、分子成像、生物统计学、负责任的研究进行和实验室管理方面的有组织的培训；以及2)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的多学科导师和顾问团队的指导，促进他向研究独立性的过渡。

 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.