MITOCHONDRIAL DNA DELETIONS IN CARDIAC SURGERY

心脏手术中的线粒体 DNA 缺失

• 批准号: 2696620
• 负责人: JAMES D MCCULLY
• 金额: $ 18.07万
• 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/2696620
• 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：（改编自研究者摘要）现在的工作主体 存在的证据表明，线粒体DNA缺陷发生在 遗传或获得性途径与心血管疾病相关， 异常此前，研究人员已经表明，线粒体 钙（[Ca 2 +]mt）积累和线粒体基因表达是 在手术诱导的全脑缺血和再灌注过程中发生改变， 这些变化与缺血后功能下降有关 在老年人中恢复，但不是成熟的心。他们还表明， 老年心脏[Ca 2 +]mt积累增加与 降低线粒体基因表达和酶活性。这些 这种现象被证明与保存减少有关， 缺血再灌注期间高能磷酸盐的再合成 老年心肌在初步调查中， 聚合酶链反应方法，PI表明，在兔 心脏mtDNA 7，436缺失的患病率增加， 全脑缺血和再灌注，这些改变与 老年人的缺血性功能恢复减少， 成熟的心在一项平行研究中， 接受心脏手术的人类患者， 结果表明，缺血再灌注增加了 线粒体DNA，436缺失。导致这些改变的病理生理学 线粒体DNA中线粒体DNA含量及其与心肌功能障碍的关系仍有待进一步研究 然而，初步研究表明，富含AT的 兔和人心脏中mtDNA 7，436缺失侧翼序列 可能是有意义的。调查人员计划调查 mtDNA缺失在临床相关动物模型和 来自心脏手术患者的人心房组织样品，以确定 导致mtDNA缺失发生率增加的机制 缺血和/或再灌注，并确定其身份和相对 线粒体DNA缺失对脑缺血后功能恢复的作用 心脏手术病人这些研究将提供以下方面的见解： 心脏病患者mtDNA缺失的患病率; 心肌老化和mtDNA缺失对手术结果的影响。 此外，这些调查将提供信息， 用于开发替代性肌保护外科手术， 优化心脏手术患者的潜在结局。