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 导致心肌梗死(MI)和心力衰竭的缺血性心脏病是发病率的主要原因 以及美国的死亡率。心肌细胞不可逆转的丢失(CMS)和过度的纤维化由前- 转化生长因子β(转化生长因子-β)和Rho相关激酶(ROCK)等纤维化信号转导途径 是导致心肌梗死后病理性心室重构的主要因素。目前还不清楚是否 促纤维化信号的激活抑制了心肌梗死后成年哺乳动物心脏的CM再生。 最近，我们的实验室证明抑制转化生长因子-β信号显著提高了效率。 将成纤维细胞重新编程为功能性CMS，这可能与转化生长因子-β信号抑制 从胚胎干细胞衍生的类胚体和心脏前体细胞中制备CMS 成人的心脏。然而，转化生长因子-β信号调节心肌细胞的确切分子机制 形成或心肌发生仍然难以捉摸，也是这一应用的重点。我们假设转化生长因子- β信号通过与表观遗传调节器的串扰来控制心肌的发生。我们的初步研究 证明转化生长因子-β信号在控制心脏转录之间的物理相互作用中的新作用 如Tbx5和表观遗传调节因子，如UTX，H3K27me3去甲基酶。进一步的研究将 确定转化生长因子-β信号轴的调节机制--表观遗传修饰 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 心肌梗塞后的心脏。在体外，我们将激活或抑制转化生长因子-β信号在表达心源性的成纤维细胞中 重编程因子和多能干细胞。我们将检验转化生长因子-β信号的假设 调节心肌生成的方式使转化生长因子-β信号的效应物，如磷酸盐- Smad2/3和心源性转录因子如Tbx5相互竞争结合和 招募染色质的表观遗传调节者。在胚胎心脏中，我们将抑制转化生长因子-β信号 全局或在特定类型的CPC中测试抑制转化生长因子-β信号转导的假设 通过调节染色质的占位促进CPC向心肌细胞分化 心脏发育过程中的修饰物。在成人心肌梗死后，我们将抑制转化生长因子-β信号 整体或在心脏成纤维细胞中，并检查重编程因子介导的心肌发生。 我们将尝试验证这样的假设，即抑制转化生长因子-β信号可促进新生血管再生。 心肌梗死后心脏的CMS。总而言之，这些体外和体内研究的结果应该会提供 对细胞信号、表观遗传调节因子和心源性因子控制的洞察 心肌发生，并应提供基础，促进新的治疗方法的开发 心脏再生的策略。