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

基本信息

  • 批准号:
    10586699
  • 负责人:
  • 金额:
    $ 38.69万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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)来源的心肌细胞(ICM)引起了极大的兴奋 承诺让受伤的心肌再生。在临床前研究中,我们已经证明了ICM具有 显著的功能益处;然而,仍然存在重大挑战,包括室性心律失常, 畸胎瘤形成,在宿主心肌植入性差。此外,可靠的再生 受伤的心肌还没有被看到。虽然还没有出现有效的永久修复战略, 旁分泌因素似乎是ICM治疗有益效果的基础。最近,我们发现了 富含线粒体的胞外小泡(M-EV),由ICM分泌。这些电动汽车有效地 通过细胞内生物能量的恢复来修复受损的心肌细胞和心肌。这个 旁分泌作用是通过线粒体转移和生物发生来增加ATP的产生。 这项提议将重塑心力衰竭(HF)治疗的未来。有明确的临床指征和需求 改善心力衰竭患者的高死亡率和高发病率。当前护理标准的缺点可能是 由于在了解HF中的生物能量失衡方面的需求尚未得到满足。平衡的破坏 能量供需之间的关系是心力衰竭发病的基础。来自心脏疾病患者的心脏组织 肥厚型、扩张型或缺血性心肌病均表现为线粒体结构异常和 尽管衰竭心脏的代谢能量需求增加,但ATP产生减少。虽然 过氧化物酶体增殖物激活受体γ辅活化子-1α(PGC-1α)是PGC-1的主要调节因子。 心衰患者心肌线粒体生物发生和功能、PGC-1α水平降低。 能量产生不足会导致心肌细胞收缩能力丧失,心肌功能障碍, 最终,失代偿的心衰。M-EV的蛋白质组学分析显示了一个新的6个富集型M-EV簇 与pGC-1α相互作用的蛋白质(PC)。PC被发现能上调能量代谢,包括氧化 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治疗方法 它通过以下3个具体目标直接针对细胞内生物能量学: 特定目的1-确认丰富的M-EV蛋白簇(PC)在线粒体生物发生中的作用。 特异性目标2:确定M-EVS在体外ICM模型中的保护作用机制 缺氧性损伤。 具体目标3:评估线粒体增强和/或生物发生在IN中的功能益处 活体小鼠慢性心肌损伤模型。 在这项研究结束后,线粒体增强和生物发生的生物能量学机制将是 在M-EVS中得到证实,可以显著和持续地恢复受损心肌。

项目成果

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PHILLIP CHUNG-MING YANG其他文献

PHILLIP CHUNG-MING YANG的其他文献

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{{ truncateString('PHILLIP CHUNG-MING YANG', 18)}}的其他基金

Patient Oriented Research in Cardiovascular Regeneration
以患者为中心的心血管再生研究
  • 批准号:
    9912812
  • 财政年份:
    2016
  • 资助金额:
    $ 38.69万
  • 项目类别:
Patient Oriented Research in Cardiovascular Regeneration
以患者为中心的心血管再生研究
  • 批准号:
    9109231
  • 财政年份:
    2016
  • 资助金额:
    $ 38.69万
  • 项目类别:
Cell Characterization and Imaging for Regenerative Therapies in Ischemic Diseases
缺血性疾病再生疗法的细胞表征和成像
  • 批准号:
    8605911
  • 财政年份:
    2012
  • 资助金额:
    $ 38.69万
  • 项目类别:
Cell Characterization and Imaging for Regenerative Therapies in Ischemic Diseases
缺血性疾病再生疗法的细胞表征和成像
  • 批准号:
    8448630
  • 财政年份:
    2012
  • 资助金额:
    $ 38.69万
  • 项目类别:
Comprehensive in vivo MRI of mouse embryonic stem cell myocardial engraftment
小鼠胚胎干细胞心肌移植的综合体内 MRI
  • 批准号:
    7693016
  • 财政年份:
    2009
  • 资助金额:
    $ 38.69万
  • 项目类别:
Comprehensive in vivo MRI of mouse embryonic stem cell myocardial engraftment
小鼠胚胎干细胞心肌移植的综合体内 MRI
  • 批准号:
    8284427
  • 财政年份:
    2009
  • 资助金额:
    $ 38.69万
  • 项目类别:
Comprehensive in vivo MRI of mouse embryonic stem cell myocardial engraftment
小鼠胚胎干细胞心肌移植的综合体内 MRI
  • 批准号:
    7921456
  • 财政年份:
    2009
  • 资助金额:
    $ 38.69万
  • 项目类别:
Comprehensive in vivo MRI of mouse embryonic stem cell myocardial engraftment
小鼠胚胎干细胞心肌移植的综合体内 MRI
  • 批准号:
    8090457
  • 财政年份:
    2009
  • 资助金额:
    $ 38.69万
  • 项目类别:
Cellular and Molecular MRI of Stem Cell Viability
干细胞活力的细胞和分子 MRI
  • 批准号:
    7350128
  • 财政年份:
    2007
  • 资助金额:
    $ 38.69万
  • 项目类别:
Cellular and Molecular MRI of Stem Cell Viability
干细胞活力的细胞和分子 MRI
  • 批准号:
    7190797
  • 财政年份:
    2007
  • 资助金额:
    $ 38.69万
  • 项目类别:

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细胞粘附分子 1 体细胞肾上腺突变对醛固酮生理和病理产生的体内和离体教训
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