Mitochondria-rich microvesicles for restoration of intracellular bioenergetics

富含线粒体的微泡用于恢复细胞内生物能

• 批准号: 10586699
• 负责人: PHILLIP CHUNG-MING YANG
• 金额: $ 38.69万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586699
• 关键词: Adrenergic beta-Antagonists; Aldosterone; Angiotensins; Bioenergetics; Biogenesis; Cardiac; Cardiac Myocytes; Cell physiology; Chronic; Citric Acid Cycle; Clinical; Congestive Heart Failure; Data; Diagnosis; Dilated Cardiomyopathy; Electron Transport; Energy Metabolism; Energy Supply; Energy-Generating Resources; Engraftment; Equilibrium; Exhibits; Future; Generations; Genome; Glycolysis; Heart; Heart failure; Hospitalization; Hypertrophic Cardiomyopathy; Hypoxia; Impairment; In Vitro; Injections; Injury; Innovative Therapy; Mediating; Messenger RNA; Metabolic; Mitochondria; Mitochondrial DNA; Modeling; Morbidity - disease rate; Mus; Myocardial dysfunction; Myocardium; Natural regeneration; Oxidative Phosphorylation; PPAR gamma; Pathogenesis; Patients; Ploidies; Production; Proteins; Proteome; Proteomics; Regimen; Renin; Reporting; Research Personnel; Respiratory physiology; Role; Shapes; Structural defect; Teratoma; Therapeutic; Tissues; Transgenic Organisms; Ventricular Arrhythmia; Work; Workload; antagonist; cell injury; extracellular vesicles; fatty acid metabolism; functional restoration; genomic profiles; improved; in vivo; induced pluripotent stem cell derived cardiomyocytes; injured; injury and repair; innovation; ischemic cardiomyopathy; loss of function; microvesicles; mortality; mouse model; myocardial injury; novel; novel therapeutic intervention; novel therapeutics; paracrine; pharmacologic; preclinical study; protective effect; protein expression; restoration; standard of care; targeted treatment; treatment strategy

PROJECT SUMMARY/ABSTRACT Induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) have generated great excitement for their promise to regenerate the injured myocardium. In pre-clinical studies, we have demonstrated that iCMs have significant functional benefit; however, substantial challenges remain, including ventricular arrhythmia, teratoma formation, and poor engraftment in the host myocardium. Furthermore, reliable regeneration of the injured myocardium has yet to be seen. While no effective strategy for permanent restoration has emerged, paracrine factors appear to underlie the beneficial effects of iCM therapy. Recently, we discovered the mitochondria-rich extracellular vesicles (M-EVs), which are secreted from the iCMs. These M-EVs effectively repair the injured cardiomyocytes and myocardium through restoration of intracellular bioenergetics. The paracrine effect is achieved by mitochondrial transfer and biogenesis to augment ATP production. This proposal will re-shape the future of heart failure (HF) therapeutics. There is clear clinical indication and need to improve the high mortality and morbidity of HF patients. The shortcoming of current standard of care may be due to the unmet need in understanding the bioenergetic imbalance in HF. The disruption of the balance between energy supply and demand underlies the pathogenesis of HF. Cardiac tissues from patients with hypertrophic, dilated, or ischemic cardiomyopathy all exhibit structural abnormalities of mitochondria and diminished ATP production despite increased metabolic energy demands in the failing heart. Although peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) serves as a master regulator of mitochondrial biogenesis and function, PGC-1α levels are decreased in the myocardium of the HF patients. Insufficient energy generation results in the loss of cardiomyocyte contractility, myocardial dysfunction, and, ultimately, decompensated HF. Proteomic analysis of M-EVs demonstrated a novel cluster of 6 enriched M-EV proteins (PC), which interact with PGC-1α. PC was found to up-regulate energy metabolism, including oxidative phosphorylation, fatty acid metabolism, and glycolysis. Therefore, we hope to develop an innovative therapy that targets the intracellular bioenergetics directly through the following 3 Specific Aims: Specific Aim 1 – Confirm the role of enriched M-EV protein cluster (PC) in mitochondrial biogenesis. Specific Aim 2: Determine the mechanism of the protective effects of M-EVs in an in vitro iCM model of hypoxic injury. Specific Aim 3: Assess the functional benefits of mitochondrial augmentation and/or biogenesis in an in vivo mouse model of chronic myocardial injury. Upon conclusion of this study, the bioenergetic mechanism of mitochondrial augmentation and biogenesis will be confirmed in M-EVs for significant and sustained restoration of the injured myocardium.

项目摘要/摘要 诱导多能干细胞（IPSC）衍生的心肌细胞（ICMS）引起了极大的兴奋 承诺再生受伤的心肌。在临床前研究中，我们证明了ICM有 重大功能益处；但是，仍然存在重大挑战，包括心律不齐， 畸胎瘤形成，宿主心肌的植入不良。此外，可靠的再生 受伤的心肌尚未看到。虽然没有出现永久性恢复的有效策略，但 旁分泌因子似乎是ICM治疗的有益作用的基础。最近，我们发现了 从ICMS分泌的富含线粒体的细胞外蔬菜（M-EV）。这些M-EV有效 通过恢复细胞内生物能学，修复受伤的心肌细胞和心肌。 通过线粒体转移和生物发生来增强ATP产生，可以实现旁分泌效应。 该建议将重新塑造心力衰竭（HF）疗法的未来。有明确的临床指示和需求 提高HF患者的高死亡率和发病率。当前护理标准的缺点可能是 由于未满足的需要了解HF中的生物能失衡。平衡的破坏 能源供应和需求之间是HF的发病机理。患者的心脏组织 肥厚，扩张或缺血性心肌病全部暴露的线粒体结构异常 ATP生产目的地的减少增加了心脏失败的代谢能量需求。虽然 过氧化物体增殖物激活的受体γ共振剂1α（PGC-1α）用作主调节剂 线粒体生物发生和功能，HF患者心肌的PGC-1α水平降低。 能量产生不足会导致心肌细胞收缩性丧失，心肌功能障碍以及，以及 最终，HF代偿失调。 M-EV的蛋白质组学分析显示了一个新的6个富集的M-EV的簇 蛋白质（PC），与PGC-1α相互作用。发现PC可以上调能量代谢，包括氧化剂 磷酸化，脂肪酸代谢和糖酵解。因此，我们希望开发一种创新的疗法 通过以下3个特定目的，直接针对细胞内生物能学： 具体目标1 - 确认富集的M-EV蛋白簇（PC）在线粒体生物发生中的作用。 特定目标2：确定M-EV在体外ICM模型中受保护作用的机制 低氧损伤。 特定目标3：评估线粒体增强和/或生物发生的功能益处 慢性心肌损伤的体内小鼠模型。 在本研究结束后，线粒体增强和生物发生的生物能机理将是 在M-EV中确认，可显着恢复受伤的心肌。