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.

项目总结/摘要 缺血性心脏病导致心肌梗死（MI）和心力衰竭是发病的主要原因 死亡率在美国。心肌细胞（CM）的不可逆损失和过度的纤维化由促纤维化蛋白原控制。 纤维化信号传导，如转化生长因子β（TGF-β）和Rho相关激酶（ROCK）通路 是导致MI后患者病理性心室重构的主要因素。目前还不知道是否 促纤维化信号传导的激活抑制MI后成年哺乳动物心脏中的CM再生。 最近，我们的实验室已经表明，抑制TGF-β信号转导显著提高了效率， 将成纤维细胞重编程为功能性CM，这可能与TGF-β信号抑制 从胚胎干细胞衍生的胚状体和心脏祖细胞（CPC）中产生CM， 成人的心然而，TGF-β信号调节心肌细胞的精确分子机制 形成或心肌发生仍然是难以捉摸的，并且是本申请的焦点。我们假设TGF- β信号通过与表观遗传调节因子的相互作用控制心肌发生。我们的初步研究 证明了TGF-β信号在控制心脏转录之间的物理相互作用中的新作用。 因子如Tbx 5和表观遗传调节因子如UTX，一种H3 K27 me 3脱甲基酶。进一步的研究将 定义TGF-β信号转导轴-表观遗传修饰调节的机制 心肌发生，以及轴在发育心脏和成人心肌发生控制中的作用 心肌梗死后的心脏在体外，我们将激活或抑制TGF-β信号在成纤维细胞表达心源性 重编程因子和多能干细胞。我们将检验TGF-β信号转导 调节心肌发生的方式，TGF-β信号的效应器，如磷- Smad 2/3和心源性转录因子如Tbx 5相互竞争结合， 为染色质募集表观遗传调节因子。在胚胎心脏中，我们将抑制TGF-β信号传导 在全球范围内或特定类型的CPC中测试抑制TGF-β信号传导的假设 通过调节染色质的占有率促进CPC分化为心肌细胞 心脏发育过程中的修饰物。在成年心肌梗死后，我们将抑制TGF-β信号传导， 全球或在心脏成纤维细胞和检查重编程因子介导的心肌发生。 我们将尝试检验抑制TGF-β信号传导促进再生的假设。 心肌梗死后心脏中的CM。总之，这些体外和体内研究的结果应该提供 深入了解细胞信号传导、表观遗传调节因子和心源性因子控制 心肌发生，并应提供基础，以促进新的治疗发展， 心脏再生的策略。