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.

项目概要/摘要 导致心肌梗塞 (MI) 和心力衰竭的缺血性心脏病是发病的主要原因 和美国的死亡率。心肌细胞（CM）的不可逆损失和由亲细胞控制的过度纤维化 纤维化信号传导，例如转化生长因子 β (TGF-β) 和 Rho 相关激酶 (ROCK) 通路 是导致心肌梗死后患者病理性心室重构的主要因素。尚不清楚是否 促纤维化信号的激活抑制成年哺乳动物心脏 MI 后的 CM 再生。 最近，我们的实验室表明，抑制 TGF-β 信号传导可显着提高效率 将成纤维细胞重编程为功能性 CM，这可能与 TGF-β 信号传导抑制这一事实有关 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难以捉摸，是本应用的重点。我们假设 TGF- β 信号传导通过与表观遗传调节因子的串扰来控制心肌生成。我们的初步研究 证明 TGF-β 信号传导在控制心脏转录之间的物理相互作用中发挥新作用 Tbx5 等因子和 UTX（一种 H3K27me3 去甲基酶）等表观遗传调节因子。进一步的研究将 定义 TGF-β 信号传导-表观遗传修饰轴的调节机制 心肌发生，以及轴在心脏发育和成人心肌发生控制中的作用 心梗后的心脏。在体外，我们将激活或抑制表达心源性成纤维细胞中的 TGF-β 信号传导 重编程因子和多能干细胞。我们将检验 TGF-β 信号传导的假设 调节心肌生成的方式是 TGF-β 信号传导的效应物，如磷酸化 Smad2/3 和心源性转录因子（例如 Tbx5）相互竞争结合并 招募染色质的表观遗传调节因子。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用促进 CPC 分化为心肌细胞 心脏发育过程中的调节剂。在心梗后的成年发情期，我们将抑制 TGF-β 信号传导 全局或心脏成纤维细胞中并检查重编程因子介导的心肌发生。 我们将尝试检验抑制 TGF-β 信号传导可增强细胞再生的假设 MI 后心脏中的 CM。总之，这些体外和体内研究的结果应该提供 对细胞信号传导、表观遗传调节剂和心源性因素控制的见解 心肌发生，并应为促进新型治疗方法的开发提供基础 心脏再生策略。