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 心脏骤停非常普遍，导致极高的死亡率。不幸的是，没有 药物治疗已被证明可以可靠地提高心脏骤停后的生存率。 心脏骤停的幸存者通常会出现全身器官损伤，需要在医院进行重症监护 医院。大多数患者的心功能下降，四分之一的患者死亡 来自心源性休克。心脏骤停后导致心功能障碍的机制之一 复苏是指心脏中，特别是线粒体中活性氧（ROS）的产生。 众所周知，线粒体 ROS 会对附近的线粒体 DNA (mtDNA) 造成损害，而线粒体 DNA 对生命活动至关重要。 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 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) 对心脏骤停小鼠模型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，已知 在许多心脏病模型中具有保护作用。 我的首要假设是心脏骤停引起的缺血再灌注损伤会导致 mtDNA 损伤 继发于线粒体 ROS 产生，导致电子传递链蛋白调节受损 心脏功能障碍。为了探索这个假设，我将追求两个具体目标。在目标 1 中，我将测试链接 使用线粒体研究心脏骤停、ROS 产生、mtDNA 损伤和心脏功能之间的关系 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 目标 2，我将测试心肌细胞中特异的 TFAM 水平是否调节心肌细胞的发育 心肌病和心脏骤停模型中的生存​​。 总之，这些目标将证明心脏骤停后 mtDNA 损伤是由以下因素介导的： 线粒体 ROS 并导致心脏骤停后心肌病。此外，他们将表明这些变化 可以通过线粒体 ROS 清除和 TFAM 操作来预防，这可能是 心脏骤停患者的新颖治疗干预措施。