Metabolic control of cellular differentiation and the fibrotic response

细胞分化和纤维化反应的代谢控制

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要目前，超过 500 万美国人患有心力衰竭，新增诊断约 50 万例每年，为了应对心脏损伤，都会出现纤维化反应，以维持结构和功能。这种愈合反应的核心是成纤维细胞向高度分化。不幸的是，许多心脏病具有慢性性质。伴随着肌成纤维细胞的持续存在和进行性纤维化，导致心脏因此，确定必要的分子机制非常重要。最近的研究表明，细胞代谢的变化是对肌成纤维细胞形成和维持的影响。细胞重塑所需的，并与支持分化的基因程序的诱导相关在许多细胞类型中，中间代谢的变化可以改变各种细胞的丰度。代谢物，其中一些对于表观遗传修饰酶的功能至关重要，例如 DNA 和事实上，已知表观遗传修饰可以沉默和去甲基化酶。促进基因转录和分化程序，这可能会引发纤维化基因的诱导因此，我们认为中间代谢的改变对于表观遗传是必要的。我们的初步数据表明，肌成纤维细胞分化需要重新编程。分化过程中发生的活性足以促进肌成纤维细胞分化，即使在缺乏此外，糖酵解的这些变化与丰度的变化有关。关键代谢物，其中一些是特定表观遗传修饰剂所需的辅助因子，特别是 α-。酮戊二酸水平在 TGF 刺激（典型纤维化激动剂）后显着增加，并且在通过相关性，我们发现已知纤维化基因的调控区域内 H3K27me2 丢失。表明 H3K27 去甲基化依赖于特定类别的 αKG 依赖性组蛋白的活性 KDM（含有组蛋白去甲基化酶的 Jumonji C 结构域）在这里，我们将同时使用代谢组学和组蛋白去甲基化酶。功能获得和丧失模型系统中的表观基因组方法来检查该过程的中心地位该项目将首次定义中间代谢的变化。与介导成纤维细胞分化的转录调控直接相关。