Autogeneic Mitochondria: Surgical Cardioprotection

自体线粒体：外科心脏保护

• 批准号: 7946214
• 负责人: JAMES D MCCULLY
• 金额: $ 43.47万
• 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/7946214
• 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）：用于心肌修复或再生的基于细胞的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/再生的机制的争论仍有待阐明。最重要的是，在细胞分离、免疫耐受、细胞移植和整合方面仍然存在困难。因此，增加细胞递送、细胞功能/存活的策略在允许通过细胞疗法成功的心肌修复/再生中是至关重要的。最近，我们已经证明，从患者自身的身体，骨骼组织中分离的自体线粒体，不受缺血的影响，然后在早期再灌注期间注射到缺血区，显著减少肌坏死（坏死和凋亡），并显著增强缺血后功能。移植的线粒体是有活力的、有呼吸能力的、维持膜电位的，在注射后存在于心肌中至少21天，并且在距注射部位显著距离处从外膜到内膜下分布。从远端骨骼肌中分离和制备自体线粒体是快速的，并且可以在< 90分钟内进行-在冠状动脉旁路移植术（CABG）和经皮冠状动脉介入治疗ST段抬高心肌梗死（PCI-STEMI）的冠状动脉血运重建的临床干预中，这是合理的时间范围。自体线粒体移植为实际应用提供了免疫学优势，而无需使用抗排斥药物治疗，并且可以用作排他性干预或在随后的自体、同种异体或异种细胞再生干预之前用作主要干预，以改善肌坏死并增强心肌功能。我们建议在临床相关的原位CABG和PCI-STEMI模型中优化自体线粒体移植用于改善肌坏死和增强心肌功能的使用;并使用生化/免疫组织化学、NMR和整合转录组学和蛋白质组学分析来确定自体线粒体移植显著增强外科心脏保护的特定机制。 公共卫生相关性：最近，我们已经证明，从患者自身的身体中分离的自体线粒体，从未受缺血影响的远端骨骼组织中分离的线粒体，然后在早期再灌注期间直接注射到心肌的缺血区中，显著减少肌坏死（坏死和凋亡），并显著增强缺血后的功能恢复。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段抬高心肌梗死的冠状动脉血运重建中，优化使用自体线粒体移植来改善肌坏死和增强心肌功能（PCI-STEMI）模型;并使用生物化学/免疫组织化学鉴定自体线粒体移植显著增强手术心脏保护的特定机制，NMR和整合转录组学和蛋白质组学分析。