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

基本信息

批准号：
10322068
负责人：
Dao-Fu Dai
金额：
$ 16.06万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322068
关键词：
5&apos -AMP-activated protein kinase ATP2A2 Acetylation Adult American Arrhythmia Award Biochemical Bioenergetics Biogenesis Biology Bradycardia Calcium Calcium Channel Cardiac Cardiac Myocytes Cardiomyopathies Cells 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 Lead 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)Nerve Degeneration Nicotinamide adenine dinucleotide Nodal Nuclear Outcome Oxidation-Reduction Pacemakers Patients Play Post-Translational Protein Processing Post-Translational Regulation Prevalence Property Protein Kinase Proteins Proteomics Publications Relaxation Role SIRT1 gene Signal Transduction Sirtuins Societies Sodium Channel Testing Text Training Treatment Failure biomechanical test cardiogenesis design disease-in-a-dish effective therapy human disease human model improved induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes insight mitochondrial dysfunction mortality mouse model mutant new technology new therapeutic target nicotinamide riboside supplementation nicotinamide-beta-riboside novel therapeutics overexpression prevent rare genetic disorder sensor sudden cardiac death

项目摘要

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.

摘要文字：大约有570万成年美国人心力衰竭，这种流行率是预计到2030年将增加25％。尽管心力衰竭治疗有所改善，包括设备治疗和心脏移植，死亡率仍然很高。心律不齐是最常见的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由于病因引起的心力衰竭功能障碍。其中，线粒体心肌病证明了线粒体功能最严重的损害。线粒体疾病是一群罕见的线粒体蛋白突变引起的遗传疾病，大多数由核DNA编码，少数由线粒体DNA。尽管只有大约40％的线粒体疾病患者暴露于心脏参与，心肌病的存在显着预测了结果不佳，至今没有有效的疗法。迫切需要新的治疗以治疗此类患者。这项研究建议操纵能量传感器信号传导以增强线粒体功能，以治疗线粒体疾病，专注于线粒体心肌病。我们的初步数据和以前的出版物建议能量传感器信号传导，包括AMP激活的蛋白激酶（AMPK）和烟酰胺腺嘌呤二核苷酸（NAD+），在线粒体疾病中保持线粒体功能也起着重要作用就像心力衰竭的发展一样。这项研究提出了操纵能量传感器信号的策略（AMPK，NAD+，SIRTUIN）在小鼠模型中提高线粒体功能并挽救心律不齐与线粒体心肌病（AIM 1）缺乏复杂的I缺乏症。为了更好地概括人类疾病，我使用人诱导的多能细胞在菜肴上对人线粒体心肌病建模的建议带有线粒体复合物I缺乏症（AIM 2）的衍生心肌细胞，并使用相同的策略营救心律不齐和心肌细胞功能障碍。培训奖提供了学习小说的绝佳机会 IP的技术，基因编辑（例如CRISPR/CAS），生物力学和电生理学的测量心肌细胞的功能参数为“菜肴中的疾病”，并扩展了我在线粒体中的训练生物学。该提议很重要，因为它提高了我们对关系的科学理解线粒体功能障碍和心力衰竭和心律不齐，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开发不可治疗的线粒体的新疗法疾病。最后，由于线粒体功能障碍在终阶段心力衰竭的各种病因中证明了在本研究中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。