MIF在调控心梗后心肌炎症反应的作用机制及其靶向干预研究

心肌梗塞是世界范围内导致心力衰竭及心源性死亡的首要病因。心梗后的自身免疫反应是损伤心肌愈合的关键要素。然而，过度的全身及局部的炎症反应将导致心脏破裂，心室扩张及心力衰竭。因此，成功调控心梗后的炎性反应需要对其机制的精确理解。近年来，本申请人的系列研究发现巨噬细胞移动抑制因子MIF在介导心梗后的炎性反应方面具有重要作用，且不同细胞来源的MIF对炎性反应及愈合过程有着截然不同的影响。本课题拟采用基因干预小鼠品系并通过骨髓移植技术构建嵌合体小鼠。在在体心梗模型中，通过检测全身及心肌的各项炎性指标，在器官、细胞以及分子水平研究MIF介导、调控心梗后全身及局部炎症反应的作用机理。同时研究心源性MIF对损伤心肌愈合的调控机制。采用针对心梗后不同MIF高峰的抗MIF治疗策略，对心肌损伤，炎性反应程度，愈合进程，心脏破裂的风险及远期心脏重塑进行系统评估，为缺血心肌的保护探索更加有效的治疗措施。

Myocardial infarction (MI) is a leading cause of heart failure and mortality worldwide and its prevalence is expected to increase with population aging. Innate immune response following MI is a necessary step for proper healing. However, excessive systemic and regional inflammatory responses lead to adverse outcome with high risk of heart rupture and severe cardiac dilatation and failure. Therefore, successful modulation of acute inflammatory responses following MI requires more precise understanding of the mechanisms involved. A great challenge to modern cardiology is to limit heart damage and preserve function after MI. Recently, our serial pioneering studies have identified that macrophage migration inhibitory factor (MIF), a well known multifunctional cytokine, plays a pivotal role in modulating post-infarct inflammation and MIF derived from different cellular sources has distinct action on post-infarct inflammation and healing. In this project, we will systemically study the underlying mechanisms by which MIF regulates post-MI inflammation and explore the therapeutic potential. First, using genetically modified mouse strains i.e. MIF gene knockout (MIFKO) mice, in vivo MI model and various methodologies, we will study how MIF activates systemic inflammation post MI. Second, applying bone marrow transplant technology, we will generate chimeric mice with MIF gene either only expressed in the heart (WT-KO) or only expressed in inflammatory cells (KO-WT). Using these chimeric mice together with MIFKO and wild type (WT) control mice, we will distinguish the role of MIF from different cellular sources in promoting regional inflammation after MI. Third, taking advantages of these genetic modified strains, we will investigate the potential mechanisms of cardiac- or leukocyte-derived MIF in regulating post-infarct healing and fibroblast biology. Finally, we will test therapeutic potential of anti-MIF strategies targeting on two different waves of MIF release following MI in protecting the heart from severe ischemic injury and preventing adverse cardiac remodeling. Results from this project will largely advance our knowledge and understanding in the role of MIF in modulating post-infarct inflammation and will provide critical information for the design of anti-inflammatory strategy targeting on MIF following acute MI.