MITOCHONDRIAL DNA DELETIONS IN CARDIAC SURGERY

心脏手术中的线粒体 DNA 缺失

• 批准号: 6184065
• 负责人: JAMES D MCCULLY
• 金额: $ 17.86万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6184065
• 关键词: aging; clinical research; functional ability; gene deletion mutation; heart surgery; human subject; laboratory rabbit; mitochondrial DNA; molecular pathology; myocardial ischemia /hypoxia; myocardium disorder; nucleic acid sequence; pathologic process; polymerase chain reaction; reperfusion

DESCRIPTION: (Adapted from investigator's abstract) A body of work now exists to suggest that mitochondrial DNA defects occurring either through inherited or acquired pathways are associated with cardiovascular abnormalities. Previously, the investigator have shown that mitochondrial calcium ([Ca2+]mt) accumulation and mitochondrial gene expression are altered during surgically induced global ischemia and reperfusion and that these alterations are associated with decreased post-ischemic functional recovery in the aged but not the mature heart. They have also shown that increased [Ca2+]mt accumulation in the aged heart was associated with decreased mitochondrial gene expression and enzyme activity. These phenomena were shown to be related to decreased preservation and resynthesis of high energy phosphates during ischemia and reperfusion in the aged myocardium. In preliminary investigations using a novel polymerase chain reaction methodology, the PI showed that in the rabbit heart the prevalence of the mtDNA7, 436 deletion is increased during global ischemia and reperfusion and that these alterations are associated with decreased pot ischemic functional recovery in the aged but not the mature heart. In a parallel study using atrial appendage tissues from human patients undergoing cardiac surgery, similar results have been obtained indicated that ischemia-reperfusion increases the prevalence of the mtDNA, 436 deletion. The pathophysiology leading to these alterations in mtDNA and their relationship to myocardial dysfunction remain to be elucidated, however, preliminary investigation would suggest that AT-rich sequences flanking the mtDNA7,436 deletions in the rabbit and human heart may be of significance. The investigators plan to investigate the relevance of mtDNA deletions in a clinically relevant animal model and in human atrial tissue samples from cardiac surgery patients to determine the mechanisms leading to increased prevalence of mtDNA deletions during ischemia and/or reperfusion and to determine the identity and relative contribution of mtDNA deletions to post-ischemia functional recovery in the cardiac surgical patient. These studies will provide insight as to: the prevalence of mtDNA deletions in the cardiac patient; the effect of myocardial aging; and the effect of mtDNA deletions on surgical outcome. In addition, these investigation will provide information which will allow for the development of alternative myoprotective surgical procedures to optimize potential outcome in cardiac surgical patients.

描述：（改编自研究者的摘要）现在的工作主体 存在表明线粒体 DNA 缺陷通过以下方式发生 遗传或获得性途径与心血管相关 异常。此前，研究人员已经证明线粒体 钙 ([Ca2+]mt) 积累和线粒体基因表达 在手术引起的全身缺血和再灌注期间发生改变 这些改变与缺血后功能下降有关 老年人可以康复，但心不成熟。他们还表明 老年心脏中 [Ca2+]mt 积累增加与 线粒体基因表达和酶活性降低。这些 现象被证明与保存减少和 缺血和再灌注期间高能磷酸盐的再合成 老化的心肌。在初步调查中使用小说 聚合酶链式反应方法，PI 表明在兔子中 心脏 mtDNA7, 436 缺失的患病率在 全身缺血和再灌注，并且这些改变是相关的 老年人的缺血性功能恢复有所下降，但老年人则不然 成熟的心。在一项使用心耳组织的平行研究中 在接受心脏手术的人类患者中，也得到了类似的结果 获得的结果表明，缺血再灌注增加了患病率 线粒体DNA，436缺失。导致这些改变的病理生理学 mtDNA 及其与心肌功能障碍的关系仍有待进一步研究 然而，初步调查表明，富含 AT 的 兔子和人类心脏中 mtDNA7,436 缺失侧翼的序列 可能具有重要意义。调查人员计划调查此事 临床相关动物模型中 mtDNA 缺失的相关性 来自心脏手术患者的人类心房组织样本，以确定 导致 mtDNA 缺失发生率增加的机制 缺血和/或再灌注并确定身份和相关性 mtDNA缺失对缺血后功能恢复的贡献 心脏手术患者。这些研究将提供以下方面的见解： 心脏病患者线粒体 DNA 缺失的患病率；的效果 心肌老化；以及线粒体DNA缺失对手术结果的影响。 此外，这些调查将提供信息，使 开发替代性肌肉保护外科手术 优化心脏手术患者的潜在结果。