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.

项目摘要/摘要 心力衰竭（HF）的共同特征是通过专业和 响应心脏损伤的分化成纤维细胞种群，称为肌纤维细胞。而肌纤维细胞 帮助维持受伤的心脏的结构完整性，并防止心室壁破裂，持久性 肌成纤维细胞导致过度纤维化和随后的心脏代偿负诺。因此，识别 心脏纤维化中肌纤维细胞分化的分子机制可能会产生新的临床靶标，以延迟 或扭转HF的发展。最近的证据表明，新陈代谢可能会驱动细胞分化 通过调节表观遗传修饰的酶，增强或静音基因与细胞相关 分化。改变的新陈代谢改变了充当底物的代谢产物的浓度 表观遗传修饰的酶，例如改变组蛋白活性的乙酰辅酶A的变化水平 乙酰转移酶（帽子）。我们的初步数据表明，糖酵解率的提高是关键特征驱动 肌纤维细胞的分化。我们确定了组蛋白去甲基化的代谢调节作为 肌纤维细胞分化，现在我们将视力转变为组蛋白乙酰化作为表观遗传学修饰 允许肌纤维细胞基因表达。该提议假设增加了乙酰辅酶A 生物合成对于分化过程中的帽子是组蛋白赖氨酸乙酰化所必需的 肌纤维细胞基因程序的激活。这项研究旨在确定新颖的治疗靶点以减轻 HF纤维化的后果。