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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：
10995416
负责人：
Dao-Fu Dai
金额：
$ 4.86万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2024
资助国家：
美国
起止时间：
2024-01-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10995416
关键词：
role energy sensor signaling mitochondrial

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.

摘要正文：大约570万美国成年人患有心力衰竭，这一患病率是预计到2030年将增长25%。尽管心力衰竭治疗有所改进，包括设备治疗和心脏移植，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各种原因引起的心力衰竭的功能障碍。其中，线粒体心肌病表现出最严重的线粒体功能损害。线粒体疾病是一组罕见的线粒体蛋白突变引起的遗传性疾病，大部分由核DNA编码，少数由线粒体DNA。尽管只有大约40%的线粒体疾病患者表现为心脏病受累，心肌病的存在显著预示着不良的结局，而且到目前为止还没有有效的治疗。迫切需要新的治疗方法来治疗这些患者。这项研究提出操纵能量感受器信号以增强线粒体功能，以治疗线粒体疾病，重点是线粒体心肌病。我们的初步数据和之前的出版物表明能量感受器信号，包括AMP激活的蛋白激酶(AMPK)和烟酰胺腺嘌呤二核苷酸(NAD+)在线粒体疾病中也起着维持线粒体功能的重要作用就像在心力衰竭发展过程中一样。这项研究提出了操纵能量传感器信号的策略 (AMPK，NAD+，sirtuin)改善线粒体功能和挽救心律失常复合体I缺乏症合并线粒体心肌病(目标1)。为了更好地概括人类疾病，我建议在培养皿上用人诱导的多能细胞建立人线粒体心肌病模型患有线粒体复合体I缺陷的来源心肌细胞(目标2)，并使用相同的策略拯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)、生物力学和电生理学测量以心肌细胞为“盘中病”的功能参数，延长我的线粒体训练生物学。这一建议具有重要意义，因为它促进了我们对线粒体功能障碍与心力衰竭和心律失常的关系及线粒体抢救方法的试验疾病。这项研究的完成可能会导致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，这项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。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Asian Americans in STEM are not a monolith.

STEM 领域的亚裔美国人并不是铁板一块。

DOI：
10.1016/j.cell.2023.06.017
发表时间：
2023
期刊：
Cell
影响因子：
64.5
作者：
Vue,Zer;Vang,Chia;Vue,Neng;Kamalumpundi,Vijayvardhan;Barongan,Taylor;Shao,Bryanna;Huang,Sunny;Vang,Larry;Vue,Mein;Vang,Nancy;Shao,Jianqiang;Coombes,CoohleenAnn;Katti,Prasanna;Liu,Kaihua;Yoshimura,Kailee;Biete,Michelle;Dai,
通讯作者：
Dai,

Characteristics of Renal Intravascular Large B-cell Lymphoma.

DOI：
10.1016/j.ekir.2022.12.001
发表时间：
2023-03
期刊：
KIDNEY INTERNATIONAL REPORTS
影响因子：
6
作者：
Rastogi, Prerna;Alrwashdeh, Audai;Caza, Tiffany;Lin, Mercury;Obeidat, Mohammad;Giannini, Gabriel;Larsen, Chris;Dai, Dao-Fu
通讯作者：
Dai, Dao-Fu

Anti-brush border antibody (ABBA)-associated renal disease.

抗刷状缘抗体（ABBA）相关的肾脏疾病。