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: 10730363
• 负责人: Stavros George Drakos
• 金额: $ 1.16万
• 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/10730363
• 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.

项目总结