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: 9888089
• 负责人: Edward Benjamin Thorp
• 金额: $ 56.49万
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888089
• 关键词: Acute; Acute myocardial infarction; Address; Animals; Apoptotic; Biological Markers; Biology; Cardiac; Cardiac Function Study; Cardiac Myocytes; Cell Death; Cell surface; Cells; Cessation of life; Clinical; Data; Development; Engineered Gene; Engineering; Excision; Family; Family member; Gene Family; Genes; Genetic Transcription; Goals; Grant; Heart; Heart Contractilities; Heart Injuries; Heart failure; Human; Immune; Immunity; Impairment; Infarction; Inflammation; Injury; Intervention; Investigation; Laboratories; MERTK gene; Measures; Metabolic; Metabolism; Mitochondria; Molecular; Molecular Target; Monitor; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocarditis; Outcome; Pathway interactions; Patients; Performance; Phagocytes; Pharmacology; Phase; Positron-Emission Tomography; Preparation; Process; Production; Progress Reports; Proteins; Proteolysis; Receptor Cell; Regulation; Reperfusion Therapy; Research; Residual state; Resistance; Resolution; Respiration; Risk; Role; Signal Pathway; Signal Transduction; Structure; TYRO3 gene; Testing; Therapeutic; Time; Tissues; Work; axl receptor tyrosine kinase; cardiac repair; cardioprotection; cell injury; clinically relevant; cytokine; fluorodeoxyglucose positron emission tomography; healing; heart function; immunoregulation; improved; in vivo; insight; macrophage; monocyte; mortality; myocardial hypoxia; novel; novel strategies; percutaneous coronary intervention; preservation; promoter; receptor; repaired; response; theories; therapeutic evaluation; tissue injury; tissue repair; tool

Thorp Project Summary Abstract-Resubmission. Heart failure after acute myocardial infarction (AMI) is a significant cause of morbidity and mortality. Though pharmacological advances have significantly reduced mortality, the residual risk of post AMI-induced heart failure is increasing. This compels the development of new approaches to preserve the integrigty of cardiac tissue after injury. The extent of tissue damage in the acute phase of AMI 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 and its expansion, which are a function of cardiomyocyte death and ineffecient tissue repair. Efficient phagocytic removal of dying cardiomyocytes by efferocytosis is critical to initiating resolving inflammation and to heart healing. For example, reduced efferocytosis of dying cardiomyocytes is directly correlated with increased morbidity and mortality post AMI. Recent studies have also shown macrophage subsets to be differentially responsible for phagocytic and repair functions in the heart. Beyond the cellular level, the molecular pathways within myocardial phagocytes that regulate efferocytosis-directed inflammation resolution in the heart, remain unknown. The Thorp laboratory has made the recent discovery that maladaptive inactivation of efferocytosis signaling pathways worsen heart repair after AMI, paving the way for a new class of molecular targets to enhance heart healing. Our studies newly reveal that the apoptotic cell receptors of the TAM family, MerTK and AXL, surprisingly act though distinct mechanisms to regulate cardiomyocyte efferocytosis and myocardial inflammation resolution. Our data in non-gene targeted mice and humans also suggest that AXL is naturally inhibited during AMI by proteolysis. These initial findings led to important new lines of investigation. This includes: (I) The degree to which AXL uniquely functions in macrophages to regulate AMI repair in the hypoxic heart, including how this may be exploited for thereapeutic intervention. (II) Novel TAM receptor-dependent and -independent immunometabolic mechanisms of efferocytosis and inflammation resolution and (III) the unknown causal role of AXL proteolysis post AMI in mice and patients. Thus, these new Aims are poised to make significant advances in the still relatively understudied process of efferocytosis in heart, efferocytic immunometabolic signaling, and the basic biology of TAM receptors. Newly created tools, including novel gene-engineered experimental animals, will assist in rigorous testing of the aforementioned principles and are of significance to both cardiac inflammation and broader principles of tissue injury.

Thorp项目摘要-重新提交。 急性心肌梗死(AMI)后心力衰竭是发病率和死亡率的重要原因 死亡率。尽管药物方面的进步显著降低了死亡率，但残留物 急性心肌梗死后心力衰竭的风险正在增加。这迫使新的 损伤后保存心肌组织完整性的方法。组织损伤的程度 在急性心肌梗死急性期是随后不良反应程度的关键决定因素 导致心脏功能受损的重塑。因此，一个重要的目标是 最大限度地减少心肌梗死面积及其扩大，这是心肌细胞死亡和 无效的组织修复。通过胞吐作用有效地吞噬死亡的心肌细胞 对启动消炎和心脏愈合至关重要。例如，减少了 死亡心肌细胞的胞吐作用与发病率的增加和 急性心肌梗死后死亡率。最近的研究也表明巨噬细胞亚群是不同的 负责心脏的吞噬和修复功能。在细胞水平之外， 心肌吞噬细胞内调节胞吐作用的分子途径 心脏中的炎症消退仍不清楚。索普实验室已经做出了 最近发现，泡饮信号通路的非适应性失活会使心脏恶化 急性心肌梗死后的修复，为促进心脏愈合的新一类分子靶点铺平了道路。 我们的研究新发现，家族的凋亡细胞受体MerTK和Ax1， 令人惊讶的是，通过不同的机制来调节心肌细胞的泡沫化和 心肌炎症消退。我们在非基因靶向的小鼠和人类中的数据也 提示AXL在急性心肌梗死过程中通过蛋白降解被自然抑制。这些初步发现导致了 重要的新调查线索。这包括：(I)AXL唯一的程度 巨噬细胞调节缺氧性心脏急性心肌梗死修复的功能，包括这可能是如何实现的 被用来进行治疗干预。(Ii)新颖的受体依赖和非依赖 吞噬和消炎的免疫代谢机制和(Iii) 急性心肌梗死后AXL蛋白分解在小鼠和患者中的未知因果作用。因此，这些新的目标 准备在仍然相对较少被研究的进程中取得重大进展 心脏的胞吐作用、胞吐免疫代谢信号与的基础生物学 感受器。新发明的工具，包括新的基因工程实验动物，将 协助对上述原则进行严格测试，并对心脏和心脏 炎症和更广泛的组织损伤原理。