Administrative supplement - Childcare

摘要 心脏骤停是非常普遍的，并导致压倒性的死亡率。不幸的是， 药物治疗已被证明可以可靠地增加心脏骤停后的存活率。 心脏骤停的幸存者通常有全身器官损伤，需要重症监护， 医院这些患者中的大多数心脏功能下降，四分之一的患者死亡 心源性休克心脏骤停后导致心功能不全的机制之一， 复苏的关键是在心脏中，特别是在线粒体中产生活性氧（ROS）。 已知线粒体ROS会对附近的线粒体DNA（mtDNA）造成损伤，这对线粒体的功能至关重要。 维持线粒体功能。我们实验室的初步工作表明， 线粒体DNA完整性，包括线粒体靶向抗氧化治疗和线粒体过表达 转录因子A（TFAM）对心脏骤停小鼠模型中的心脏功能具有保护作用。 TFAM是一种调节mtDNA表达、包装和拷贝数的核基因， 在许多心脏病模型中具有保护作用。 我的总体假设是心脏骤停引起的缺血再灌注损伤导致线粒体DNA损伤 继发于线粒体ROS产生，导致电子传递链蛋白调节受损， 心功能不全为了探讨这个假设，我将追求两个具体目标。在目标1中，我将测试链接 心脏骤停、ROS产生、mtDNA损伤和心功能之间的关系， 在心脏骤停的体内小鼠模型以及缺血-再灌注的细胞模型中的抗氧化剂。在 目的2，我将测试心肌细胞中TFAM的水平是否特异性地调节心肌细胞的发展。 心肌病和心脏骤停模型中的存活率。 总之，这些目标将证明心脏骤停后mtDNA损伤是由 线粒体活性氧和有助于后逮捕心肌病。此外，他们将表明，这些变化 可以通过清除线粒体ROS和操纵TFAM来预防，TFAM可能是 心脏骤停患者的新型治疗干预。

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.