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

基本信息

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
项目类别：
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

项目摘要

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中和患病的心脏中。负责响应生理和病理的响应细胞能量产生刺激。线粒体调节系统由严格的转录因子和协同激活因子，这些共激活因子依赖涉及米孔氏菌生物发生，维持的基因表达和呼吸capace。生物能学很复杂，它仍然没有构成协调的响应生理和病理刺激。最近在骨骼肌肉中确定了pers1（“肌肉1中的pgc-1和err常规”）为一个新型的肌肉特异性蛋白质，定期用线粒体氧化胶囊诱导。运动，并且PERS1的表达增加增强了线粒体生物发生，氧化能力，和小鼠骨骼肌肉的疲劳性。了解线粒体肌病和肌肉萎缩。此外，从未被征服。目前未知病理生理学：（1）PERS1在心脏中高度表达，并在小鼠失败中被下调心脏和心力衰竭患者；人IPS细胞衍生的心肌细胞的成熟；导致线粒体呼吸能力降低。 PERS1控制线粒体函数ERRα的调节，这是众所周知的转录因子这策划了线粒体生物精品中基因的表达。该应用将利用遗传动物模型和最先进的多系统方法为了概念化，我们对心脏中线粒体生物能学的理解。预计工作将证明Perm1是线粒体生物合成和心脏中的能量学是ERRα途径。将PERS1递送到心脏可预防线粒体损伤和心脏功能障碍压力超过负荷引起的心力衰竭的设置。心脏中线粒体调节的转录辅助因子将深刻推动我们的对心脏代谢的了解，并可能建议采用新的治疗方法来进行心力衰竭。