The role of energy sensor signaling in mitochondrial cardiomyopathy

摘要：大约570万美国成年人患有心力衰竭， 预计到2030年将增长25%。尽管心力衰竭治疗（包括器械治疗）有所改善， 和心脏移植，死亡率仍然很高。心律失常是最常见的 心力衰竭患者的死亡原因。我们和其他人已经证明了线粒体的作用， 由于各种病因引起的心力衰竭的功能障碍。其中，线粒体心肌病 证明了最严重的线粒体功能受损。线粒体疾病是一组罕见的 由于线粒体蛋白质突变引起的遗传性疾病，大多数由核DNA编码，少数由 线粒体DNA虽然只有大约40%的线粒体疾病患者表现出心脏 参与，心肌病的存在显着预测不良结果，迄今为止，没有 有效的治疗。迫切需要新的治疗方法来治疗这些患者。本研究提出 操纵能量传感器信号传导以增强线粒体功能，以治疗线粒体疾病。 疾病，重点是线粒体心肌病。我们的初步数据和以前的出版物表明， 能量传感器信号，包括AMP激活的蛋白激酶（AMPK）和烟酰胺腺嘌呤， 二核苷酸（NAD+）在线粒体疾病中对维持线粒体功能也起重要作用 如在心力衰竭的发展过程中。本研究提出了操纵能量传感器信号的策略 (AMPK，NAD+，sirtuin）改善线粒体功能并挽救心律失常的小鼠模型。 复合物I缺乏伴线粒体心肌病（目的1）。为了更好地概括人类疾病，我 建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 衍生的心肌细胞与线粒体复合物I缺陷（目的2），并使用相同的策略，以挽救 心律失常和心肌细胞功能障碍。培训奖提供了一个学习小说的绝佳机会 iPS技术、基因编辑（如CRISPR/cas）、生物力学和电生理测量 心肌细胞的功能参数的“疾病在一个盘子”，并扩大我的训练，在线粒体 生物学这一建议意义重大，因为它促进了我们对生物多样性与环境之间关系的科学理解。 线粒体功能障碍与心力衰竭和心律失常的关系及检测线粒体的方法 疾病这项研究的完成可能会导致开发新的治疗无法治疗的线粒体 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学中是明显的， 这项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

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.