The Role of Acetyl-CoA Metabolism in Epigenetic Regulation of Myofibroblast Differentiation

乙酰辅酶A代谢在肌成纤维细胞分化的表观遗传调控中的作用

• 批准号: 10684688
• 负责人: Michael Lazaropoulos
• 金额: $ 5.27万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684688
• 关键词: ATP Citrate (pro-S)-Lyase; Acetate-CoA Ligase; Acetyl Coenzyme A; Acetylation; Adult; Agreement; Anabolism; Antibodies; Automobile Driving; Biochemical; Biological Assay; Biological Availability; Cardiac; Cell Lineage; Cessation of life; Chromatin; Chronic; Clinical; Coupled; Data; Deposition; Development; Enzymes; Epigenetic Process; Extracellular Matrix; Family member; Fibroblasts; Fibrosis; Functional disorder; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Transcription; Glucose; Glycolysis; Healthcare; Heart; Heart Injuries; Heart failure; Histologic; Histone Acetylation; Histones; Impairment; Inflammation; Injury; Label; Lysine; Mediating; Medicine; Metabolic; Metabolic Pathway; Metabolism; Modeling; Modification; Molecular; Mus; Myocardial; Myocardial dysfunction; Myofibroblast; Oxygen; Palmitates; Pathway interactions; Phenotype; Population; Process; Production; Regulation; Reporter; Role; Rupture; Testing; Transcriptional Activation; Ventricular; Vision; antagonist; care burden; chromatin immunoprecipitation; chromatin remodeling; cofactor; coronary fibrosis; demethylation; epigenetic regulation; extracellular; histone acetyltransferase; in vivo; in vivo evaluation; inducible Cre; interstitial; ischemic injury; metabolomics; new therapeutic target; next generation sequencing; novel; permissiveness; pharmacologic; prevent; programs; promoter; response; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT A common feature of heart failure (HF) is excessive extracellular matrix deposition by a specialized and differentiated fibroblast population, known as myofibroblasts, in response to cardiac injury. While myofibroblasts help to maintain the structural integrity of the injured heart and prevent ventricular wall rupture, persistence of myofibroblasts results in excessive fibrosis and subsequent cardiac decompensation. Therefore, identifying molecular mechanisms of myofibroblast differentiation in cardiac fibrosis could yield novel clinical targets to delay or reverse the development of HF. Recent evidence suggests metabolism may drive cellular differentiation through the modulation of epigenetic-modifying enzymes that enhance or silence genes associated with cellular differentiation. Altered metabolism changes the concentration of metabolites that act as substrates for epigenetically modifying enzymes, such as the changing levels of acetyl-CoA that alter the activity of histone acetyltransferases (HAT). Our preliminary data indicate that increased glycolytic rate is a key feature driving myofibroblast differentiation. We identified metabolic regulation of histone demethylation as a feature of myofibroblast differentiation and we now turn our sights to histone acetylation as an epigenetic modification permissive of myofibroblast gene expression. This proposal hypothesizes that increased acetyl-CoA biosynthesis is necessary for histone lysine acetylation by HATs during differentiation for the transcriptional activation of the myofibroblast gene program. This study seeks to identify novel therapeutic targets to mitigate the consequences of fibrosis in HF.

项目总结/摘要 心力衰竭（HF）的一个共同特征是由一种专门的和特异性的细胞外基质沉积过多。 分化的成纤维细胞群体，称为肌成纤维细胞，响应心脏损伤。而肌成纤维细胞 有助于维持受损心脏的结构完整性，防止心室壁破裂， 肌成纤维细胞导致过度纤维化和随后的心脏代偿失调。因此，识别 心肌纤维化中肌成纤维细胞分化的分子机制可能产生新的临床靶点， 或逆转HF的发展。最近的证据表明代谢可能会驱动细胞分化 通过调节表观遗传修饰酶，增强或沉默与细胞凋亡相关的基因， 分化改变的代谢改变了作为底物的代谢物的浓度， 表观遗传修饰酶，例如改变组蛋白活性的乙酰辅酶A水平的变化 乙酰转移酶（HAT）。我们的初步数据表明，糖酵解速率的增加是一个关键特征， 肌成纤维细胞分化我们将组蛋白去甲基化的代谢调节确定为 肌成纤维细胞分化，我们现在把目光转向组蛋白乙酰化作为表观遗传修饰 允许肌成纤维细胞基因表达。该提案假设乙酰辅酶A的增加 在分化过程中，HAT对组蛋白赖氨酸的乙酰化是生物合成所必需的， 肌成纤维细胞基因程序的激活。这项研究旨在确定新的治疗靶点，以减轻 HF中纤维化的后果。