Perm1 is a Novel Regulator of Cardiac Energetics and Function

Perm1 是一种新型的心脏能量和功能调节剂

• 批准号: 10547828
• 负责人: Stavros George Drakos
• 金额: $ 46.48万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-20 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547828
• 关键词: Ablation; Acceleration; Adult; Anabolism; Animal Genetics; Animal Model; Bioenergetics; Biogenesis; Biological Assay; Cardiac; Cardiac Myocytes; Cell Nucleus; Cells; Citric Acid Cycle; Complex; Congestive Heart Failure; Crista ampullaris; Data; Defect; Development; Down-Regulation; EFRAC; ERR1 protein; Epigenetic Process; Exercise; Exhibits; Fatigue; Feedback; Functional disorder; Gene Delivery; Gene Expression; Genes; Genetic Models; Genetic Transcription; Global Change; Heart; Heart Diseases; Heart failure; Heterozygote; Human; Impairment; Knock-out; Knowledge; Link; Luciferases; Maintenance; Metabolic; Mitochondria; Mitochondrial Myopathies; Mus; Muscle; Muscular Atrophy; Myocardial; Myocardial dysfunction; Oxidative Phosphorylation; PPAR gamma; Pathologic; Pathway interactions; Patients; Phenotype; Physiological; Production; Proteins; Recovery; Regulation; Regulatory Pathway; Reporter Genes; Resistance; Respiration; Response Elements; Role; Shortening Fraction; Signal Pathway; Skeletal Muscle; Stimulus; Stress Tests; System; Testing; Time; Transcription Coactivator; Work; chromatin immunoprecipitation; cofactor; density; energy balance; functional adaptation; heart function; heart metabolism; histone methyltransferase; induced pluripotent stem cell derived cardiomyocytes; interdisciplinary approach; knock-down; novel; novel therapeutic intervention; peer; postnatal development; pressure; promoter; response; therapeutic target; transcription factor

PROJECT SUMMARY Energy metabolic reprogramming occurs in the developing and diseased hearts. Mitochondria are responsible for coordinating cellular energy production in response to physiological and pathological stimuli. The mitochondrial regulatory system is highly regulated by several transcription factors and coactivators that orchestrate the expression of genes involved in mitochondrial biogenesis, maintenance, and respiration capacity. However, the transcriptional regulatory machinery in mitochondrial bioenergetics is complex, and it is still not completely understood how mitochondria coordinately respond to physiological and pathological stimuli. Perm1 (“PGC-1 and ERR regulator in muscle 1”) was recently identified in skeletal muscle, as a novel muscle-specific protein that regulates mitochondrial oxidative capacity. Perm1 is induced by exercise, and the increased expression of Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in mouse skeletal muscle. These findings point to a new path towards understanding mitochondrial myopathies and muscle atrophies. However, the role of Perm1 in the heart has never been investigated. Moreover, the regulatory mechanism of Perm1 in mitochondrial function is currently unknown. Our preliminary data suggest the significant role of Perm1 in cardiac pathophysiology: (1) Perm1 is highly expressed in the heart and is downregulated in the mouse failing heart and in patients with heart failure; (2) Perm1 expression is increased during differentiation and maturation in human iPS cell-derived cardiomyocytes; (3) Perm1 knockdown in cultured cardiomyocytes leads to reduced mitochondrial respiration capacity. Furthermore, our preliminary data suggest that Perm1 controls mitochondrial function through the regulation of ERRα, a well-known transcription factor that orchestrates the expression of genes in mitochondrial bioenergetics. This application will leverage a genetic animal model and state-of-the art multisystems approach to conceptually advance our understanding of mitochondrial bioenergetics in the heart. Specifically, this work is expected to demonstrate that Perm1 is a critical regulator of mitochondrial biosynthesis and energetics in the heart through the ERRα pathway. Furthermore, this study will determine if gene delivery of Perm1 to the heart protects against mitochondrial impairment and cardiac dysfunction in the setting of pressure-overload-induced heart failure. Conclusive evidence that Perm1 is a novel transcriptional cofactor of the mitochondrial regulatory pathway in the heart will profoundly advance our knowledge of cardiac metabolism, and may suggest new therapeutic approaches for heart failure.

项目摘要 能量代谢重编程发生在发育和患病的心脏中。线粒体是 负责协调细胞的能量生产，以响应生理和病理 刺激。线粒体调节系统受几种转录因子的高度调节， 协同激活因子，其协调参与线粒体生物发生，维持， 呼吸能力。然而，线粒体中的转录调节机制 生物能量学很复杂，线粒体如何协调反应仍不完全清楚 对生理和病理刺激的反应 Perm 1（“PGC-1 and ERR regulator in muscle 1”）最近在骨骼肌中被鉴定，作为一种免疫调节因子。 一种新型肌肉特异性蛋白，可调节线粒体氧化能力。Perm 1是由 运动，Perm 1的表达增加增强线粒体生物合成，氧化能力， 和小鼠骨骼肌的抗疲劳性。这些发现指出了一条新的道路， 了解线粒体肌病和肌肉萎缩。然而，Perm 1在心脏中的作用 从未被调查过此外，Perm 1在线粒体功能中的调节机制是 目前未知。我们的初步数据表明Perm 1在心脏中发挥重要作用 病理生理学：（1）Perm 1在心脏中高表达，在心衰小鼠中表达下调 （2）Perm 1表达在分化过程中增加， 人iPS细胞衍生的心肌细胞中的成熟;（3）培养的心肌细胞中的Perm 1敲低 导致线粒体呼吸能力降低。此外，我们的初步数据表明， Perm 1通过调节ERRα（一种众所周知的转录因子）来控制线粒体功能 在线粒体生物能量学中协调基因的表达。 该应用程序将利用遗传动物模型和最先进的多系统方法 从概念上推进我们对心脏线粒体生物能量学的理解。具体来说， 这项工作有望证明Perm 1是线粒体生物合成的关键调节因子， 通过ERRα途径在心脏中产生能量。此外，这项研究将确定基因是否 将Perm 1递送至心脏可防止线粒体损伤和心脏功能障碍， 压力超负荷诱发的心力衰竭。证明Perm 1是一部小说的确凿证据 心脏线粒体调节途径的转录辅因子将深刻地推进我们的研究。 心脏代谢的知识，并可能为心力衰竭提出新的治疗方法。