Administrative supplement - Childcare

行政补助 - 儿童保育

• 批准号: 10493714
• 负责人: Cody Rutledge
• 金额: $ 0.23万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10493714
• 关键词: Acute; Administrative Supplement; Affect; American; Anoxia; Antioxidants; Automobile Driving; Bioenergetics; Biological Process; Cardiac; Cardiac Myocytes; Cardiogenic Shock; Cardiomyopathies; Cardiopulmonary Resuscitation; Cell model; Chronic; Clinical; DNA; DNA Damage; DNA Repair Enzymes; Data; Depressed mood; Development; Diffuse; Disease model; Dose; EFRAC; Electron Transport; Electrons; Genes; Genetic; Genome; Heart; Heart Arrest; Heart Diseases; Hospitals; Hypertrophy; Impairment; Inflammation; Injury; Intensive Care; Intervention; Ischemia; Lead; Link; Mediating; Methods; Mitochondria; Mitochondrial DNA; Mitochondrial Matrix; Modeling; Molecular; Morphology; Multiple Organ Failure; Myocardial dysfunction; Neurological status; Nuclear; Organ; Outcome; Oxidants; Oxygen; Pathway interactions; Patients; Pharmacologic Substance; Pharmacology; Production; Proteins; Reactive Oxygen Species; Regulation; Reperfusion Injury; Reperfusion Therapy; Resuscitation; Secondary to; Stress; Structure; Survivors; Symptoms; Syndrome; Testing; Therapeutic; Transgenic Mice; Work; antioxidant therapy; associated symptom; cardioprotection; factor A; heart function; heart preservation; improved; improved outcome; in vitro Model; in vivo; mortality; mouse model; mtTF1 transcription factor; natural hypothermia; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; oxidative damage; preservation; prevent; survival outcome; symptomatic improvement; transcription factor

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.

抽象的 突然的心脏骤停非常普遍，导致压倒性的死亡率。不幸的是，没有 已证明心脏骤停后可靠地增加生存率的药理学疗法。 突然心脏骤停的幸存者通常会有系统性的器官损害，需要重症监护 医院。这些患者的大多数患者的心脏功能降低，其中四分之一的患者死亡 来自心脏病性休克。心脏骤停后驱动心脏功能障碍的机制之一和 复苏是心脏中的活性氧（ROS）的产生，尤其是在线粒体中。 已知线粒体ROS会损害附近的线粒体DNA（mtDNA），这对于至关重要 维持线粒体功能。我们实验室的初步工作表明，旨在保存的方法 mtDNA完整性，包括线粒体靶向抗氧化剂疗法和线粒体的过表达 转录因子A（TFAM）在心脏骤停的小鼠模型中对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，已知为 在许多心脏病模型中保护性。 我的总体假设是，心脏骤停导致mtDNA损害导致心脏骤停的局部性再灌注损伤 线粒体ROS的继发性产生，导致电子传输链蛋白质调节受损和 心脏功能障碍。为了探讨这一假设，我将追求两个具体的目标。在AIM 1中，我将测试链接 使用线粒体之间的心脏骤停，ROS产生，mtDNA损伤和心脏功能 心脏骤停的体内小鼠模型中的抗氧化剂以及缺血再灌注的细胞模型。在 AIM 2，我将测试心肌细胞中TFAM的水平是否专门调节 心肌病模型中的心肌病和生存。 这些目的共同证明心脏骤停后的mtDNA损伤是由 线粒体ROS，并导致后心肌病后。此外，他们将表明这些变化 线粒体ROS清除和TFAM操纵可以防止 心脏骤停患者的新型治疗干预措施。