Administrative supplement - Childcare

摘要 心脏骤停非常普遍，并导致压倒性的死亡。不幸的是，没有 已被证明能可靠地提高心脏骤停后的存活率的药物疗法。 心脏骤停的幸存者通常有系统性器官损伤，需要重症监护 医院。这些患者中的大多数都有心功能减退，其中四分之一死亡。 死于心源性休克。导致心脏骤停后心功能不全的机制之一 复苏是在心脏，特别是在线粒体中产生的活性氧物种(ROS)。 已知线粒体ROS会对附近的线粒体DNA(MtDNA)造成损害，而线粒体DNA对 维持线粒体的功能。我们实验室的初步工作表明，旨在保存 线粒体DNA完整性，包括线粒体靶向抗氧化治疗和线粒体过度表达 转录因子A(TFAM)在心脏骤停小鼠模型中对心脏功能具有保护作用。 TFAM是一种核基因，调节mtDNA的表达、包装和拷贝数，已知的是 在许多心脏病模型中具有保护作用。 我的主要假设是，心脏骤停引起的缺血再灌注损伤会导致线粒体DNA损伤。 继发于线粒体ROS的产生，导致电子传递链蛋白调节受损和 心脏功能不全。为了探索这一假设，我将追求两个具体目标。在目标1中，我将测试链接 利用线粒体在心脏骤停、ROS产生、线粒体DNA损伤和心脏功能之间的关系 抗氧化剂在心脏骤停的活体小鼠模型以及缺血-再灌注的细胞模型中的应用。在……里面 目的2，我将测试心肌细胞中TFAM的特异性水平是否调节 心脏骤停模型中的心肌病和存活率。 总之，这些目标将证明心脏骤停后线粒体DNA损伤是由 线粒体ROS参与心脏骤停后心肌病的发生。此外，他们将表明，这些变化 可通过清除线粒体ROS和操纵TFAM来预防，这可能是TFAM的靶点 心脏骤停患者的新治疗干预措施。

Abstract Sudden cardiac arrest is highly prevalent and results in overwhelming mortality. Unfortunately, there are no pharmacologic therapies that have been shown to reliably increase survival after sudden cardiac arrest. Survivors of sudden cardiac arrest typically have systemic organ damage requiring intensive care in the hospital. The majority of these patients have reduced cardiac function and one quarter of these patients die from cardiogenic shock. One of the mechanisms driving cardiac dysfunction after cardiac arrest and resuscitation is the production of reactive oxygen species (ROS) in the heart, particularly in the mitochondria. Mitochondrial ROS is known to cause damage to nearby mitochondrial DNA (mtDNA), which are crucial for maintaining mitochondrial function. Preliminary work in our lab has shown that methods aimed at preserving mtDNA integrity, including mitochondrial targeted antioxidant therapy and overexpression of mitochondrial transcription factor A (TFAM), are protective to cardiac function in a mouse model of sudden cardiac arrest. TFAM is a nuclear gene that regulates mtDNA expression, packaging, and copy number and is known to be protective in a number of heart disease models. My overarching hypothesis is that ischemia-reperfusion injury from cardiac arrest results in mtDNA damage secondary to mitochondrial ROS production, leading to impaired electron transport chain protein regulation and cardiac dysfunction. To explore this hypothesis, I will pursue two specific aims. In Aim 1, I will test the link between cardiac arrest, ROS production, mtDNA damage, and cardiac function using mitochondrial antioxidants in an in vivo mouse model of cardiac arrest as well as a cellular model of ischemia-reperfusion. In Aim 2, I will test whether the levels of TFAM specifically in the cardiomyocytes modulate the development of cardiomyopathy and survival in the cardiac arrest model. Together, these aims will demonstrate that mtDNA damage following cardiac arrest is mediated by mitochondrial ROS and contributes to post-arrest cardiomyopathy. Further, they will show that these changes can be prevented by mitochondrial ROS scavenging and manipulation of TFAM, which may be targets for novel therapeutic interventions in cardiac arrest patients.