Mitophagy pathways in cellular cross-talk in the myocardium

心肌细胞串扰中的线粒体自噬途径

• 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
• 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

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.

心肌梗死（MI）导致的缺血性心肌病和心力衰竭是最常见的心脏病之一。 美国退伍军人发病率和死亡率的原因。在缺血性心肌病中，持续 并且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。因此，我们认为， 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因子影响心肌细胞的结构和功能 自治和非自治机制。心脏巨噬细胞越来越被认为是 在压力下驱动促炎信号的主要免疫细胞类型。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MI后时期，浸润的外周单核细胞分化成巨噬细胞， 假定与常驻心脏巨噬细胞一起发挥双重作用，其特征是亲- 炎症信号传导和吞噬细胞清除早期死亡细胞，并向抗- 炎症信号传导促进修复阶段。在已发表的VA MERIT支持的研究中，我们有 揭示了巨噬细胞中溶酶体功能受损作为促炎信号传导驱动的证据。 我们的研究进一步证明了刺激巨噬细胞溶酶体生物合成程序的功效， TFEB的激活，自噬-溶酶体途径的主要调节因子，在产生表型转换中， 巨噬细胞和促进MI后愈合。在平行的研究中，我们发现了一个重要的作用， 心肌细胞中TRAF 2参与选择性溶酶体降解途径--生理性线粒体自噬 它可以去除受损的线粒体，以防止线粒体DNA泄漏，并抑制无菌性炎症。 心肌在这个建议中，我们将研究TRAF 2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心肌细胞的细胞串扰。 心肌处于稳态和应激状态。我们的初步数据表明，TRAF 2发挥作用的假设 通过促进巨噬细胞线粒体自噬和25- 羟基胆固醇抑制炎性小体活化，维持心肌稳态。的确，我们的 初步研究表明，使用遗传方法的可诱导巨噬细胞TRAF 2消融诱导了 心肌细胞肥大，左心室肥大和收缩功能障碍，以及增加的炎性 心肌细胞浸润我们已经获得了试剂，并开展了合作，以测试 假说.在具体的目标，我们将评估的后果损失的TRAF 2在巨噬细胞上， 炎症信号在具体目标2中，我们将评估巨噬细胞中TRAF 2缺失的后果。 对心肌细胞线粒体自噬的影响，并进行机制研究，以了解心肌细胞的作用， 线粒体自噬现象。在目标3中，我们将定义25-羟基胆固醇生成在 心肌中的巨噬细胞-肌细胞串扰。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。驾驭巨噬细胞 线粒体自噬和氧化固醇信号传导具有减轻炎症和治疗缺血性疾病的潜力。 心肌病占所有心力衰竭病例负担的2/3。