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.

索普项目摘要摘要归纳。 急性心肌梗塞（AMI）后心力衰竭是发病率和 死亡。尽管药理学进步显着降低了死亡率，但残留 AMI引起的心力衰竭的风险正在增加。这迫使新的发展 损伤后保留心脏组织整合的方法。组织损伤的程度 在AMI的急性阶段是随后不良程度的关键决定因素 重塑导致心脏性能受损。因此，一个重要的目标是 最小化梗塞大小及其膨胀，这是心肌细胞死亡和 无效组织修复。有效地通过吞噬作用吞噬垂死的心肌细胞的吞噬细胞是 对解决炎症和心脏愈合至关重要。例如，减少 垂死心肌细胞的肿瘤病与发病率的增加直接相关 死亡率后AMI。最近的研究还表明巨噬细胞亚群是差异的 负责心脏中的吞噬和修复功能。超出细胞水平， 调节吞噬作用指导的心肌吞噬细胞内的分子途径 心脏中的炎症分辨率仍然未知。索普实验室使 最近发现，反常胞症信号传导途径的不良适应性失活使心脏恶化 AMI后修复，为新的分子靶标铺平了道路，以增强心脏愈合。 我们的研究新发现，TAM家族，MERTK和AXL的凋亡细胞受体， 令人惊讶地采取了调节心肌细胞吞噬作用的不同机制和 心肌炎症解决方案。我们在非基因靶向小鼠和人类中的数据 建议通过蛋白水解在AMI期间自然抑制AXL。这些初步发现导致 重要的新调查线。这包括：（i）Axl独特的程度 在巨噬细胞中的功能调节低氧心脏的AMI修复，包括如何使用 利用治疗干预。 （ii）新型TAM受体依赖性和非依赖性 炎症和炎症解决方案的免疫代谢机制和（iii） AXL蛋白水解后AMI在小鼠和患者中的未知因果作用。因此，这些新目标 有望在仍然相对低估的过程中取得重大进步 心脏的肿瘤病，efferocytic免疫代谢信号传导和TAM的基本生物学 受体。新创建的工具，包括新型基因引导的实验动物，将 协助对上述原则进行严格测试，并且对这两种心脏都有意义 炎症和组织损伤的更广泛原则。