Autogeneic Mitochondria: Surgical Cardioprotection

自体线粒体：外科心脏保护

• 批准号: 8284454
• 负责人: JAMES D MCCULLY
• 金额: $ 43.07万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284454
• 关键词: Apoptosis; Biochemical; Biological Preservation; Blood; Cardiac; Cell Separation; Cell Therapy; Cell physiology; Cells; Clinical; Clinical effectiveness; Coronary; Coronary Artery Bypass; Endocardium; Engraftment; Harvest; Heart; Immune Tolerance; In Situ; Injection of therapeutic agent; Intervention; Investigation; Ischemia; Location; Logistics; Membrane Potentials; Mitochondria; Modeling; Modification; Myocardial; Myocardial Infarction; Myocardial tissue; Myocardium; Natural regeneration; Necrosis; Needles; Operative Surgical Procedures; Paracrine Communication; Patients; Pharmacotherapy; Population; Preparation; Proteins; Proteomics; Recovery of Function; Reperfusion Therapy; Respiration; Route; Site; Skeletal Muscle; Syringes; Techniques; Temperature; Time; Transcript; Transplantation; Xeno; autocrine; base; clinical application; clinical efficacy; clinically relevant; inorganic phosphate; percutaneous coronary intervention; practical application; progenitor; public health relevance; regenerative; repaired; skeletal tissue; stem cell population; transcriptomics

DESCRIPTION (provided by applicant): Cell-based therapies for myocardial repair or regeneration have shown great potential; however, debate as to the efficacy of specific cell populations, the logistics of cell harvesting and expansion, the mechanisms of cell- based myocardial repair/regeneration remain to be elucidated. Most importantly difficulties over cell isolation, immune tolerance, cellular engraftment and integration remain. Therefore strategies to augment cell delivery, cell function/survival are crucial in permitting successful myocardial repair/regeneration through cellular therapy. Recently, we have demonstrated that autogeneic mitochondria isolated from the patient's own body, from skeletal tissue, unaffected by ischemia and then injected into the ischemic zone during early reperfusion significantly decreases myonecrosis (necrosis and apoptosis) and significantly enhance post-ischemic function. The transplanted mitochondria are viable, respiration competent, maintain membrane potential, are present in the myocardium for at least 21 days after injection and are distributed from the epi- to the sub- endocardium at significant distance from the site of injection. The isolation and preparation of autogeneic mitochondria from remote skeletal muscle is rapid and can be performed in < 90 min. - a time frame reasonable within the clinical interventions of both coronary artery bypass grafting (CABG) and percutaneous coronary intervention for coronary revascularization for ST segment elevation myocardial infarction (PCI-STEMI). Autogeneic mitochondrial transplantation provides immunological advantages for practical application without the use of anti-rejection drug therapy and could be used either as an exclusive intervention or as a primary intervention prior to subsequent auto-, allo- or xeno-geneic cellular regenerative interventions to ameliorate myonecrosis and enhance myocardial function. We propose to optimize the use of autogeneic mitochondrial transplantation for the amelioration of myonecrosis and enhancement of myocardial function in the clinically relevant in situ CABG and PCI-STEMI model; and to identify the specific mechanism(s) through which autogenic mitochondrial transplantation significantly enhances surgical cardioprotection using biochemical /immunohistochemical, NMR and integrated transcriptomic and proteomic analysis. PUBLIC HEALTH RELEVANCE: Recently, we have demonstrated that autogeneic mitochondria isolated from the patient's own body, from remote skeletal tissue unaffected by ischemia, and then directly injected into the ischemic zone of the myocardium during early reperfusion, significantly decrease myonecrosis (necrosis and apoptosis) and significantly enhance post-ischemic functional recovery. In this application we propose to optimize the use of autogeneic mitochondrial transplantation for the amelioration of myonecrosis and enhancement of myocardial function in the clinically relevant in situ coronary artery bypass grafting (CABG) and percutaneous coronary intervention for coronary revascularization for ST segment elevation myocardial infarction (PCI-STEMI) model; and to identify the specific mechanism(s) through which autogenic mitochondrial transplantation significantly enhances surgical cardioprotection using biochemical /immunohistochemical, NMR and integrated transcriptomic and proteomic analysis.

描述（由申请人提供）：基于细胞的心肌修复或再生疗法已显示出巨大的潜力；然而，关于特定细胞群的功效、细胞收获和扩增的后勤、基于细胞的心肌修复/再生机制的争论仍有待阐明。最重要的是，细胞分离、免疫耐受、细胞植入和整合方面的困难仍然存在。因此，增强细胞递送、细胞功能/存活的策略对于通过细胞治疗成功进行心肌修复/再生至关重要。最近，我们证明，从患者自身骨骼组织中分离出的自体线粒体不受缺血影响，然后在早期再灌注期间注射到缺血区，可显着减少肌坏死（坏死和细胞凋亡）并显着增强缺血后功能。移植的线粒体具有活性、有呼吸能力、维持膜电位、注射后在心肌中存在至少21天，并且从心外膜分布到心内膜下，与注射部位相距很远。从远程骨骼肌中分离和制备自体线粒体的速度很快，并且可以在 < 90 分钟内完成。 - 冠状动脉旁路移植术 (CABG) 和经皮冠状动脉介入治疗 ST 段抬高型心肌梗死 (PCI-STEMI) 冠状动脉血运重建的临床干预中合理的时间范围。自体线粒体移植为实际应用提供了免疫学优势，无需使用抗排斥药物治疗，并且可以用作排他性干预措施，也可以用作后续自体、同种异体或异种细胞再生干预之前的主要干预措施，以改善肌坏死和增强心肌功能。我们建议在临床相关的原位CABG和PCI-STEMI模型中优化使用自体线粒体移植来改善肌坏死和增强心肌功能；并利用生化/免疫组织化学、核磁共振以及综合转录组和蛋白质组分析来确定自体线粒体移植显着增强外科心脏保护的具体机制。 公共健康相关性：最近，我们证明，从患者自身、未受缺血影响的远端骨骼组织中分离自体线粒体，然后在早期再灌注期间直接注射到心肌缺血区，可显着减少心肌坏死（坏死和细胞凋亡）并显着增强缺血后功能恢复。在本申请中，我们建议在临床相关的原位冠状动脉旁路移植术（CABG）和经皮冠状动脉介入治疗ST段抬高型心肌梗死（PCI-STEMI）模型中优化使用自体线粒体移植来改善肌坏死和增强心肌功能；并利用生化/免疫组织化学、核磁共振以及综合转录组和蛋白质组分析来确定自体线粒体移植显着增强外科心脏保护的具体机制。