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

基本信息

批准号：
10311072
负责人：
Edward Benjamin Thorp
金额：
$ 55.04万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/10311072
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 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 repair function repaired response theories therapeutic evaluation tissue injury tissue repair tool

项目摘要

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.

索普项目摘要摘要重新提交。急性心肌梗塞 (AMI) 后的心力衰竭是发病率和死亡率的重要原因死亡。尽管药理学进步显着降低了死亡率，但残留的 AMI 后诱发心力衰竭的风险正在增加。这迫使新的开发损伤后保持心脏组织完整性的方法。组织损伤的程度 AMI 急性期的不良反应是后续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梗塞面积及其扩张，这是心肌细胞死亡和心肌细胞死亡的函数组织修复效率低下。通过胞吞作用有效吞噬去除垂死的心肌细胞是对于开始解决炎症和心脏愈合至关重要。例如，减少死亡心肌细胞的胞吞作用与发病率的增加直接相关 AMI 后的死亡率。最近的研究还表明巨噬细胞亚群存在差异负责心脏的吞噬和修复功能。超越细胞水平，心肌吞噬细胞内调节胞吞作用定向的分子途径心脏炎症的消退仍然未知。索普实验室制造了最近发现胞吞作用信号通路的适应不良失活会导致心脏恶化 AMI 后的修复，为增强心脏愈合的新型分子靶点铺平了道路。我们的研究最新揭示了 TAM 家族的凋亡细胞受体 MerTK 和 AXL，令人惊讶的是通过不同的机制来调节心肌细胞胞吞作用和心肌炎症消退。我们在非基因靶向小鼠和人类中的数据也表明 AXL 在 AMI 期间通过蛋白水解作用自然受到抑制。这些初步发现导致重要的新调查路线。这包括： (I) AXL 的独特程度巨噬细胞在缺氧心脏中调节 AMI 修复的功能，包括其机制用于治疗干预。 (II) 新型 TAM 受体依赖性和非依赖性胞吞作用和炎症消退的免疫代谢机制以及（III） AMI 后 AXL 蛋白水解在小鼠和患者中的因果作用尚不清楚。因此，这些新目标准备在仍然相对不足的研究过程中取得重大进展心脏中的胞吞作用、胞吞免疫代谢信号传导以及 TAM 的基础生物学受体。新创建的工具，包括新型基因工程实验动物，将有助于严格测试上述原则，对心脏和心脏都有重要意义炎症和更广泛的组织损伤原理。