Efferocytosis Directed Inflammation Resolution and Repair in the Hypoxic Heart

胞吞作用引导缺氧心脏的炎症消退和修复

• 批准号: 8670424
• 负责人: Edward Benjamin Thorp
• 金额: $ 38.63万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670424
• 关键词: Acute; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Autoantigens; Biology; CD47 gene; Cardiac; Cardiac Myocytes; Cell Death; Cells; Cessation of life; Code; Color; Data; Development; Disease; Eating; Excision; Family member; Goals; Head; Heart; Heart failure; Human; Hyperlipidemia; Hypoxia; Hypoxia Inducible Factor; Immune; Infarction; Inflammation; Intervention; Investigation; Ischemia; Laboratories; Ligands; Location; MERTK gene; Maps; Measures; Mediating; Mediator of activation protein; Molecular; Molecular Target; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Necrosis; Oxygen; Pathway interactions; Performance; Perfusion; Phagocytes; Phase; Positioning Attribute; Protein Isoforms; Proteolysis; Publishing; Receptor Cell; Receptor Inhibition; Receptor Signaling; Regulation; Reperfusion Therapy; Research Personnel; Residual state; Resistance; Resolution; Risk; Risk Factors; Role; Scheme; Signal Pathway; Signal Transduction; Site; Surface; Testing; Time; Tissues; Ventricular Remodeling; Wound Healing; base; cell type; clinically relevant; heart cell; heart function; hypoxia inducible factor 1; insight; macrophage; monocyte; mortality; novel; novel strategies; promoter; public health relevance; receptor; repaired

DESCRIPTION (provided by applicant): Heart failure after myocardial infarction (MI) is a significant cause of morbidity and mortality. Though pharmacological advances have significantly reduced mortality, the residual risk of post MI-induced heart failure is increasing. This necessitates development of new approaches to preserve heart function. The extent of tissue damage in the acute phase of MI is a critical determinant of the degree of subsequent adverse remodeling that leads to impaired cardiac performance. As such, an important goal is to minimize infarct size, which is a function of cardiomyocyte (CM) death. Efficient phagocytic removal of dying CMs by efferocytosis is critical to initiating resolving inflammation and promoting heart repair. Importantly, reduced phagocytic clearance of dying CMs is directly correlated with increased morbidity and mortality post MI. Recent studies have shown monocyte subsets to be differentially responsible for phagocytic and repair functions in the heart. Beyond the cellular level, the molecular pathways within myocardial phagocytes, required for efferocytosis- directed inflammation resolution in the heart, remain unknown. My laboratory has made the discovery that inactivation of efferocytosis signaling pathways worsen heart repair after MI, paving the way for new a new class of molecular targets to promote wound healing in the heart. Our studies show that suppression of CM "don't eat me" ligands enhance engulfment by phagocytes, and that the apoptotic cell receptor MERTK, is required for CM efferocytosis. Our data in non-gene targeted mice and humans indicate MERTK is naturally inactivated during MI by proteolysis and hypoxia inducible factors (HIFs) and importantly, murine MERTK deficiency increases adverse myocardial ventricular remodeling and promotes heart failure after MI. These data implicate apoptotic cell receptors and CM don't-eat-me ligands as candidates for defective efferocytosis post MI. These initial results led to several new lines of investigation, which are the focus of this proposal, including (I) the degree to which MERTK-dependent efferocytosis and proteolysis drives the extent of post MI repair in the setting of risk factors suh as hyperlipidemia and clinically-relevant reperfusion, (II) MERTK- dependent and independent mechanisms of efferocytosis and inflammation resolution during hypoxia, and (III) novel CM interactions with M?s.

描述（由申请人提供）：心肌梗塞（MI）后的心力衰竭是发病和死亡的重要原因。尽管药理学进步显着降低了死亡率，但心肌梗死后诱发心力衰竭的残余风险正在增加。这就需要开发新的方法来保护心脏功能。心肌梗死急性期组织损伤的程度是随后导致心脏功能受损的不良重塑程度的关键决定因素。因此，一个重要的目标是最大限度地减少梗塞面积，这是心肌细胞（CM）死亡的一个功能。通过胞吞作用有效吞噬去除垂死的 CM 对于启动解决炎症和促进心脏修复至关重要。重要的是，垂死的 CM 吞噬清除率的降低与 MI 后发病率和死亡率的增加直接相关。最近的研究表明，单核细胞亚群对心脏的吞噬和修复功能有不同的作用。除了细胞水平之外，心肌吞噬细胞内胞吞作用引导的心脏炎症消退所需的分子途径仍然未知。我的实验室发现，胞吞作用信号通路的失活会恶化心肌梗死后的心脏修复，为新一类促进心脏伤口愈合的分子靶点铺平了道路。我们的研究表明，抑制 CM“别吃我”配体可增强吞噬细胞的吞噬作用，并且凋亡细胞受体 MERTK 是 CM 胞吞作用所必需的。我们在非基因靶向小鼠和人类中的数据表明，MERTK 在 MI 期间通过蛋白水解和缺氧诱导因子 (HIF) 自然失活，重要的是，小鼠 MERTK 缺乏会增加不良心肌心室重塑并促进 MI 后心力衰竭。这些数据表明凋亡细胞受体和 CM 别吃我配体是 MI 后胞吞作用缺陷的候选者。这些初步结果导致了几个新的研究方向，这是本提案的重点，包括（I）在高脂血症和临床相关再灌注等危险因素的情况下，MERTK依赖性胞吞作用和蛋白水解作用驱动心肌梗死后修复程度的程度，（II）缺氧期间MERTK依赖性和独立的胞吞作用和炎症消退机制，以及（III） CM 与 M?s 的新颖互动。