Mitophagy pathways in cellular cross-talk in the myocardium

心肌细胞串扰中的线粒体自噬途径

基本信息

批准号：
10486506
负责人：
Abhinav Diwan
金额：
--
依托单位：
ST. LOUIS VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-10-01 至 2026-09-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10486506
关键词：
25-hydroxycholesterol Ablation Acute Adult Affect Aging Anti-Inflammatory Agents Attenuated Automobile Driving Autophagocytosis Biogenesis Cardiac Cardiac Myocytes Cardiomyopathies Cd68 Cell Death Cells Cellular Infiltration Chest Cholesterol Collaborations Data Defect Degradation Pathway Development Disease Enzymes Excision Functional disorder Generations Genetic Transcription Heart failure Homeostasis Hypertrophy Immune Impairment Incidence Infiltration Inflammasome Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Injury Ischemia Left Left Ventricular Hypertrophy LoxP-flanked allele Lysosomes Macrophage Maintenance Mediating Mitochondria Mitochondrial DNA Mixed Function Oxygenases Molecular Morbidity - disease rate Mus Muscle Cells Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Pathogenesis Pathway interactions Peripheral Phagocytes Phase Phenotype Physiological Play Population Population Group Prevalence Production Publishing Reagent Reperfusion Injury Reperfusion Therapy Role Shapes Signal Transduction Sterility Stress Structure TRAF2 gene Tamoxifen Testing Therapeutic United States Ventricular Ventricular Remodeling Veterans Wild Type Mouse age group aging population cell type enantiomer genetic approach healing ischemic cardiomyopathy knock-down military veteran monocyte mortality prevent programs restoration restraint translational approach

项目摘要

Myocardial infarction (MI) with resultant ischemic cardiomyopathy and heart failure rank among the leading causes of morbidity and mortality among Veterans in the United States. In ischemic cardiomyopathy, sustained and unregulated inflammatory signaling is recognized as a driver of heart failure pathogenesis. Therefore, understanding the crosstalk between immune cells and cardiac myocytes has the potential to inform therapeutic strategies. Immune cells in the myocardium affect cardiac myocyte structure and function via cell autonomous and non-autonomous mechanisms. Cardiac macrophages are increasingly recognized as the dominant immune cell type driving pro-inflammatory signaling under stress. On the other hand, studies also point to critical homeostatic roles for resident cardiac macrophages in maintenance of cardiac structure and function. Indeed, in the post-MI period, infiltrated peripheral monocytes differentiate into macrophages and are postulated to play a dual role in concert with the resident cardiac macrophages, characterized by pro- inflammatory signaling and phagocytic removal of dead cells in the early phase and a shift towards anti- inflammatory signaling to promote reparative phase. In published VA MERIT-supported studies, we have uncovered evidence for impaired lysosome function in macrophages as a driver of pro-inflammatory signaling. Our studies further demonstrated the efficacy of stimulating the macrophage lysosome biogenesis program by activation of TFEB, a master regulator of autophagy-lysosome pathway, in engendering a phenotypic switch in macrophages and promoting post-MI healing. In parallel studies, we have uncovered an essential role for TRAF2 in cardiac myocytes in executing physiologic mitophagy, a selective lysosomal degradative pathway that removes damaged mitochondria to prevent mitochondrial DNA leak and suppress sterile inflammation in the myocardium. In this proposal, we will examine the role of TRAF2 and mitophagy in macrophages in shaping myocardial homeostasis; to understand how targeting mitophagy affects cellular crosstalk in the myocardium in homeostasis and under stress. Our preliminary data suggest the hypothesis that TRAF2 plays an essential role in macrophages by facilitating macrophage mitophagy and generation of 25- hydroxycholesterol to restrain inflammasome activation, to maintain myocardial homeostasis. Indeed, our preliminary studies demonstrate that inducible macrophage TRAF2 ablation using genetic approaches induces cardiac myocyte hypertrophy, left ventricular hypertrophy and systolic dysfunction, and increased inflammatory cell infiltration in the myocardium. We have acquired reagents and developed collaborations to test the hypothesis. In specific aim, we will evaluate the consequences of loss of TRAF2 in macrophages on inflammatory signaling. In specific aim 2, we will evaluate the consequences of loss of TRAF2 in macrophages on cardiac myocyte mitophagy, and perform mechanistic studies to understand the role of cardiac myocyte mitophagy in the observed phenotype. In aim 3, we will define the role of 25-hydroxycholesterol generation in macrophage-myocyte crosstalk in the myocardium. Successful completion of these studies will define subcellular mechanisms of macrophage-myocyte crosstalk in the myocardium. Harnessing macrophage mitophagy and oxysterol signaling has the potential to mitigate inflammation and treat ischemic cardiomyopathy that contributes to 2/3rds of all heart failure case burden.

心肌梗塞 (MI) 及其导致的缺血性心肌病和心力衰竭位居首要美国退伍军人发病和死亡的原因。在缺血性心肌病中，持续不受调节的炎症信号传导被认为是心力衰竭发病机制的驱动因素。所以，了解免疫细胞和心肌细胞之间的串扰有可能提供信息治疗策略。心肌中的免疫细胞通过细胞影响心肌细胞的结构和功能自主和非自主机制。心脏巨噬细胞越来越被认为是在压力下驱动促炎信号传导的优势免疫细胞类型。另一方面，研究还指出常驻心脏巨噬细胞在维持心脏结构中的关键稳态作用功能。事实上，在心肌梗死后时期，浸润的外周单核细胞分化为巨噬细胞并被假定与常驻心脏巨噬细胞协同发挥双重作用，其特征是亲炎症信号传导和早期死亡细胞的吞噬清除以及向抗- 炎症信号促进修复阶段。在已发表的 VA MERIT 支持的研究中，我们发现了巨噬细胞中溶酶体功能受损作为促炎信号传导驱动因素的证据。我们的研究进一步证明了通过刺激巨噬细胞溶酶体生物发生程序的功效 TFEB（自噬-溶酶体途径的主要调节因子）的激活，导致表型转换巨噬细胞并促进心肌梗死后愈合。在平行研究中，我们发现了一个重要的作用心肌细胞中 TRAF2 执行生理性线粒体自噬（一种选择性溶酶体降解途径）去除受损的线粒体，防止线粒体 DNA 泄漏并抑制无菌炎症心肌。在本提案中，我们将研究 TRAF2 和线粒体自噬在巨噬细胞中的作用塑造心肌稳态；了解靶向线粒体自噬如何影响细胞串扰心肌处于稳态和应激状态。我们的初步数据表明 TRAF2 发挥作用的假设通过促进巨噬细胞线粒体自噬和 25- 的产生，在巨噬细胞中发挥重要作用羟基胆固醇抑制炎症小体活化，维持心肌稳态。确实，我们的初步研究表明，使用遗传方法消除诱导型巨噬细胞 TRAF2 可以诱导心肌细胞肥大、左心室肥大和收缩功能障碍以及炎症增加心肌细胞浸润。我们已经购买了试剂并开展了合作来测试假设。具体目标是，我们将评估巨噬细胞中 TRAF2 缺失对细胞的影响。炎症信号传导。在具体目标 2 中，我们将评估巨噬细胞中 TRAF2 缺失的后果心肌细胞线粒体自噬，并进行机制研究以了解心肌细胞的作用观察到的表型中的线粒体自噬。在目标 3 中，我们将定义 25-羟基胆固醇生成在心肌中巨噬细胞-心肌细胞的串扰。成功完成这些研究将定义心肌中巨噬细胞-肌细胞串扰的亚细胞机制。利用巨噬细胞线粒体自噬和氧甾醇信号传导具有减轻炎症和治疗缺血的潜力心肌病占所有心力衰竭病例负担的 2/3。