Metabolic control of cellular differentiation and the fibrotic response

细胞分化和纤维化反应的代谢控制

• 批准号: 10094236
• 负责人: Andrew A Gibb
• 金额: $ 6.74万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094236
• 关键词: Acute; Affect; Agonist; American; Biochemical; Biological Assay; Biological Models; Carbon; Cardiac; Cardiovascular Diseases; Cessation of life; ChIP-seq; Chronic; Cicatrix; Collagen; Congestive Heart Failure; DNA; Data; Development; Diagnosis; Differentiation and Growth; Enzymes; Epigenetic Process; Extracellular Matrix Proteins; Failure; Fibroblasts; Fibrosis; Gene Expression; Genes; Genetic; Genetic Transcription; Glucose; Glutamine; Glycolysis; Heart; Heart Diseases; Heart Injuries; Heart failure; Histones; Inflammation; Investigation; Label; Link; Lysine; Maintenance; Measurement; Mediating; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Methylation; Methyltransferase; Modification; Molecular; Monitor; Muscle Cells; Myocardial Infarction; Myocardial dysfunction; Myofibroblast; Nature; Nucleic Acid Regulatory Sequences; Oxygen; Pathology; Pathway interactions; Pentosephosphate Pathway; Pharmacology; Process; Pyruvate; Radiolabeled; Regulation; Reporting; Signal Transduction; Stimulus; Structure; Testing; Transcriptional Regulation; alpha ketoglutarate; cell type; cofactor; coronary fibrosis; demethylation; epigenome; epigenomics; experimental study; extracellular; gene induction; healing; histone demethylase; histone methylation; histone methyltransferase; loss of function; metabolic rate; metabolomics; novel therapeutic intervention; novel therapeutics; nucleotide metabolism; programs; response; response to injury; ribosome profiling

PROJECT SUMMARY/ABSTRACT Currently, more than 5 million Americans suffer from heart failure with approximately 500,000 new diagnoses each year. In response to cardiac injury, a fibrotic response arises in an effort to maintain the structural and functional integrity of the heart. Central to this healing response is the differentiation of fibroblasts to highly specialized synthetic and contractile myofibroblasts. Unfortunately, the chronic nature of many cardiac diseases is accompanied by the persistence of myofibroblasts and progressive fibrosis contributing to cardiac decompensation and eventual failure. Therefore, it is important to identify the molecular mechanisms necessary for myofibroblast formation and maintenance. Recent studies suggest that changes in cellular metabolism are required for cellular remodeling and are associated with the induction of gene programs to support differentiation in numerous cell types. Interestingly, changes in intermediary metabolism can alter the abundance of various metabolites, some of which are essential to the function of epigenetic-modifying enzymes, such as DNA and histone methyltransferases and demethylases. Indeed, epigenetic modifications are known to both silence and promote gene transcription and differentiation programs, which may instigate the induction of the fibrotic gene program. Therefore, we hypothesize that changes in intermediary metabolism are necessary for the epigenetic reprogramming required for myofibroblast differentiation. Our preliminary data suggest that increased glycolytic activity, as occurs during differentiation, is sufficient to promote myofibroblast differentiation, even in the absence of pro-fibrotic stimuli. In addition, these changes in glycolysis are associated with alterations in the abundance of key metabolites, some of which are required cofactors for specific epigenetic modifiers. In particular, α- ketoglutarate levels are significantly increased upon TGF stimulation (canonical fibrotic agonist) and in correlation we find a loss of H3K27me2 within the regulatory regions of known fibrotic genes. Preliminary data suggests that H3K27 demethylation is dependent on the activity of a specific class of αKG-dependent, histone KDMs (Jumonji C-domain containing histone demethylases). Here we will employ both metabolomic and epigenomic approaches in gain- and loss-of-function model systems to examine the centrality of this process in myofibroblast differentiation. This project will be the first to define how changes in intermediary metabolism are directly linked to the transcriptional regulation mediating fibroblast differentiation.

项目总结/文摘