The role of energy sensor signaling in mitochondrial cardiomyopathy

能量传感器信号在线粒体心肌病中的作用

• 批准号: 10543982
• 负责人: Dao-Fu Dai
• 金额: $ 11.2万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543982
• 关键词: 5' -AMP-activated protein kinase; ATP2A2; Acceleration; Acetylation; Adult; American; Arrhythmia; Award; Biochemical; Bioenergetics; Biogenesis; Biology; Bradycardia; Calcium; Calcium Channel; Cardiac; Cardiac Myocytes; Cardiomyopathies; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Cytochrome c Reductase; DNA; Data; Deacetylase; Deacetylation; Development; Devices; Dilated Cardiomyopathy; Disease; Doctor of Philosophy; Economic Burden; Electrophysiology (science); Etiology; Exhibits; Failure; Functional disorder; Genes; Goals; Heart; Heart Diseases; Heart Transplantation; Heart failure; High Prevalence; Human; Hypertrophic Cardiomyopathy; Impairment; Intervention; Ion Channel; Knowledge; Learning; Left ventricular non-compaction; Link; Mechanics; Mediating; Metabolic; Methods; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Mitochondrial Proteins; Mitochondrial complex I deficiency; Modeling; Morbidity - disease rate; Mus; Mutate; Mutation; Myocardial dysfunction; NADH; NADH dehydrogenase (ubiquinone); Nicotinamide adenine dinucleotide; Nodal; Nuclear; Outcome; Oxidation-Reduction; Pacemakers; Patients; Play; Post-Translational Protein Processing; Post-Translational Regulation; Prevalence; Property; Proteins; Proteomics; Publications; Relaxation; Role; SIRT1 gene; Signal Transduction; Sirtuins; Societies; Sodium Channel; Testing; Text; Training; Treatment Failure; biomechanical test; design; disease-in-a-dish; effective therapy; human disease; human model; improved; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; insight; mitochondrial cardiomyopathies; mitochondrial dysfunction; mortality; mouse model; mutant; neurodegenerative phenotype; new technology; new therapeutic target; nicotinamide riboside supplementation; nicotinamide-beta-riboside; novel therapeutics; overexpression; prevent; rare genetic disorder; sensor; sudden cardiac death

ABSTRACT TEXT: Approximately 5.7 million adult Americans have heart failure and this prevalence is projected to increase 25% by 2030. Despite improvement in heart failure treatment, including device therapy and cardiac transplantation, the mortality rate remains high. Cardiac arrhythmia is among the most common cause of mortality in heart failure patients. We and others have demonstrated the roles of mitochondrial dysfunction in heart failure due to various etiologies. Among these, mitochondrial cardiomyopathy demonstrates the most severe impairment of mitochondrial function. Mitochondrial disease is a group of rare genetic disorder due to mutation of mitochondrial proteins, most encoded by nuclear DNA and a few by mitochondrial DNA. Although only approximately 40% of patients with mitochondrial disease exhibit cardiac involvement, the presence of cardiomyopathy significantly predicts poor outcome and to date there is no effective therapy. Novel therapeutics is urgently needed to treat such patients. This study proposes manipulation of energy sensor signaling to enhance mitochondrial function, in order to treat mitochondrial disease, focusing on mitochondrial cardiomyopathy. Our preliminary data and previous publications suggest that energy sensor signaling, including AMP-activated protein kinase (AMPK) and nicotinamide adenine dinucleotide (NAD+), play an important role to maintain mitochondrial function in mitochondrial disease as well as during development of heart failure. This study proposes strategies of manipulating energy sensor signaling (AMPK, NAD+, sirtuin) to improve mitochondrial function and to rescue cardiac arrhythmia in a mouse model of complex I deficiency with mitochondrial cardiomyopathy (Aim 1). To better recapitulate human disease, I propose to model human mitochondrial cardiomyopathy on a dish, using human induced pluripotent cell derived cardiomyocytes with mitochondrial complex I deficiency (Aim 2) and use the same strategies to rescue arrhythmia and cardiomyocyte dysfunction. The training award provides an excellent opportunity to learn novel technology of iPS, gene editing (such as CRISPR/cas), measurement of biomechanics and electrophysiology of cardiomyocytes as functional parameter of “disease in a dish”, and extend my training in mitochondrial biology. This proposal is significant because it advances our scientific understanding of the relationship of mitochondrial dysfunction and heart failure and arrhythmia and test the method to rescue mitochondrial disease. Completion of this study may lead to development of novel therapy for untreatable mitochondrial disease. Finally, since mitochondrial dysfunction is evident in various etiologies of end-stage heart failure, the mitochondrial protective strategies proposed in this study may also be beneficial in other types of heart diseases.

摘要：大约 570 万美国成年人患有心力衰竭，患病率 预计到 2030 年将增加 25%。尽管心力衰竭治疗（包括器械治疗）有所改善 以及心脏移植，死亡率仍然很高。心律失常是最常见的心律失常之一 心力衰竭患者死亡的原因。我们和其他人已经证明了线粒体的作用 各种病因引起的心力衰竭的功能障碍。其中，线粒体心肌病 表明线粒体功能受损最严重。线粒体疾病是一组罕见的疾病 由于线粒体蛋白突变引起的遗传性疾病，大多数由核 DNA 编码，少数由线粒体蛋白编码 线粒体DNA。尽管只有约 40% 的线粒体疾病患者表现出心脏病症状 参与，心肌病的存在显着预示着不良结果，迄今为止还没有 有效的治疗。迫切需要新的疗法来治疗此类患者。本研究提出 操纵能量传感器信号传导以增强线粒体功能，从而治疗线粒体 疾病，重点关注线粒体心肌病。我们的初步数据和之前的出版物表明 能量传感器信号传导，包括 AMP 激活蛋白激酶 (AMPK) 和烟酰胺腺嘌呤 二核苷酸 (NAD+) 在线粒体疾病中维持线粒体功能也发挥着重要作用 如心力衰竭的发展过程中。这项研究提出了操纵能量传感器信号的策略 （AMPK、NAD+、sirtuin）可改善小鼠模型中的线粒体功能并挽救心律失常 复合物 I 缺乏症导致线粒体心肌病（目标 1）。为了更好地概括人类疾病，我 提议使用人类诱导多能细胞在培养皿上模拟人类线粒体心肌病 具有线粒体复合物 I 缺陷的衍生心肌细胞（目标 2）并使用相同的策略来挽救 心律失常和心肌细胞功能障碍。培训奖提供了学习新奇的绝佳机会 iPS技术、基因编辑技术（如CRISPR/cas）、生物力学和电生理学测量 心肌细胞作为“培养皿中的疾病”的功能参数，并扩展我在线粒体方面的训练 生物学。这个提议很重要，因为它增进了我们对两者关系的科学理解。 线粒体功能障碍与心力衰竭和心律失常并测试挽救线粒体的方法 疾病。这项研究的完成可能会导致针对无法治疗的线粒体的新疗法的开发 疾病。最后，由于线粒体功能障碍在终末期心力衰竭的各种病因中都很明显，因此 本研究提出的线粒体保护策略也可能对其他类型的心脏有益 疾病。