Mechanisms for cell signaling in the control of cardiomyogenesis

控制心肌发生的细胞信号传导机制

• 批准号: 9317530
• 负责人: Kunhua Song
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317530
• 关键词: Address; Adult; Binding; Biochemistry; Bioinformatics; Cardiac; Cardiac Myocytes; Cardiac development; Cellular biology; Chromatin; Complement Factor B; Data; Development; Economic Burden; Embryo; Embryonic Heart; Epigenetic Process; Fibroblasts; Fibrosis; Foundations; Genes; Genomics; Goals; Health; Health system; Heart; Heart failure; Histones; In Vitro; Laboratories; Lead; Mediating; Modification; Molecular; Morbidity - disease rate; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Natural regeneration; Pathologic; Pathway interactions; Patients; Pluripotent Stem Cells; Production; Proteomics; Recruitment Activity; Regulation; Research; Rho-associated kinase; Role; Signal Pathway; Signal Transduction; Stem cells; Testing; Therapeutic; Transforming Growth Factors; Ventricular Remodeling; base; cardiac regeneration; cardiogenesis; cost; embryonic stem cell; experimental study; in vivo; insight; mortality; novel; novel therapeutics; repaired; transcription factor

Project Summary/Abstract Ischemic heart disease resulting in myocardial infarction (MI) and heart failure is the leading cause of morbidity and mortality in the USA. Irreversible loss of cardiomyocytes (CMs) and excessive fibrosis governed by pro- fibrotic signaling such as transforming growth factor β (TGF-β) and Rho-associated kinase (ROCK) pathways are major factors contributing to pathological ventricular remodeling in patients post-MI. It is not known whether activation of pro-fibrotic signaling inhibits CM regeneration in adult mammalian hearts following MI. Recently, our laboratory has shown that suppression of TGF-β signaling dramatically enhances the efficiency of reprogramming fibroblasts into functional CMs, which is likely related to the fact that TGF-β signaling inhibits production of CMs from embryonic stem cell-derived embryoid bodies, and cardiac progenitor cells (CPCs) in adult hearts. However, the precise molecular mechanisms by which TGF-β signaling regulates cardiomyocyte formation or cardiomyogenesis remain elusive and are the focus of this application. We hypothesize that TGF- β signaling controls cardiomyogenesis through crosstalk with epigenetic regulators. Our preliminary studies demonstrate novel roles for TGF-β signaling in the control of physical interaction between cardiac transcription factors such as Tbx5 and epigenetic regulators such as UTX, an H3K27me3 demethylase. Further studies will define the mechanisms by which the axis of TGF-β signaling-epigenetic modifications regulates cardiomyogenesis, and the roles of the axis in the control of cardiomyogenesis in developing heart and adult hearts post-MI. In vitro, we will activate or inhibit TGF-β signaling in fibroblasts expressing cardiogenic reprogramming factors, and pluripotent stem cells. We will test the hypothesis that TGF-β signaling regulates cardiomyogenesis in a manner that the effectors of TGF-β signaling such as phosphor- Smad2/3 and cardiogenic transcription factors, such as Tbx5 compete with each other for binding and recruiting epigenetic regulators to chromatin. In embryonic hearts, we will suppress TGF-β signaling globally or in specific types of CPCs to test the hypothesis that suppression of TGF-β signaling promotes differentiation of CPCs into cardiomyocytes by regulating occupancy of the chromatin modifiers during cardiac development. In adult heats post-MI, we will suppress TGF-β signaling globally or in cardiac fibroblasts and examine reprogramming factors-mediated cardiomyogenesis. We will attempt to test the hypothesis that suppression of TGF-β signaling enhances regeneration of CMs in the heart following MI. Together, results from these in vitro and in vivo studies should provide insights into cell signaling, epigenetic regulators and cardiogenic factors controlling cardiomyogenesis, and should provide the foundation to facilitate development of novel therapeutic strategies for heart regeneration.

项目摘要/摘要 缺血性心脏病导致心肌梗塞（MI）和心力衰竭是发病率的主要原因 和在美国的死亡率。心肌细胞（CMS）的不可逆转损失，超过了纤维化 纤维化信号传导，例如转化生长因子β（TGF-β）和Rho相关激酶（岩石）途径 是MI后患者的患者心室重塑的主要因素。不知道是否 MI后，促纤维化信号的激活抑制成人哺乳动物心脏的CM再生。 最近，我们的实验室表明，TGF-β信号的抑制大大提高了效率 将成纤维细胞重编程成功能性CM，这可能与TGF-β信号抑制的事实有关 从胚胎干细胞衍生的胚胎体和心脏祖细胞（CPC）中产生CM 成人心。但是，TGF-β信号传导调节心肌细胞的精确分子机制 形成或心肌发生仍然难以捉摸，是该应用的重点。我们假设TGF- β信号传导通过与表观遗传调节剂的串扰控制心肌生成。我们的初步研究 展示了TGF-β信号传导在心脏转录之间进行物理相互作用中的新作用 TBX5和表观遗传调节剂（例如UTX），H3K27me3脱甲基酶等因素。进一步的研究将会 定义TGF-β信号传导 - 遗传修饰的轴的机制调节 心肌生成，以及轴控制心脏和成人心脏切开的作用 心之后的心。在体外，我们将激活或抑制表达心源的成纤维细胞中的TGF-β信号传导 重编程因子和多能干细胞。我们将测试TGF-β信号传导的假设 以TGF-β信号（例如磷酸）的影响的方式调节心脏作用 SMAD2/3和心源转录因子，例如TBX5互相竞争以结合和 招募表观遗传调节剂到染色质。在胚胎心脏中，我们将抑制TGF-β信号传导 全球或特定类型的CPC，以测试抑制TGF-β信号的假设 通过调节染色质占用率 心脏发育过程中的修饰符。在MI后成人热量中，我们将抑制TGF-β信号传导 全球或心脏成纤维细胞中，并检查了重编程因子介导的心肌发生。 我们将尝试检验以下假设：TGF-β信号传导的抑制会增强 MI之后心脏中的CMS。这些体外和体内研究的结果应提供 对细胞信号传导，表观遗传调节剂和心源性因素的见解 心脏病生成，应为促进新疗法的发展提供基础 心脏再生策略。