Integrating Transcriptome Reprogramming Into Cardiac Plasticity Regulatory Mechanisms

项目摘要 心肌细胞的程序性末端分化对于重组心脏的结构和功能至关重要 满足基本生理需求的功能。其中许多差异化机制在以下情况下重新部署 在缺血性损伤或心脏病的情况下。而末端分化是基本的 心脏功能这种命运的改变与心肌细胞几乎完全停止增殖有关， 这是治疗缺血性心脏病的主要障碍之一--缺乏有效的 使纤维化心脏重新肌肉化的治疗策略。许多差异化机制在以下情况下重新部署 损伤，但尚不清楚这种反应是适应性的还是病理性的，从而理解了 遗传信息建立和维持心肌细胞分化提高了我们目前对基础知识的了解 心脏生理学，并提供对心脏再生和疾病的见解。我们所知道的很多关于 末端分化来自于在DNA和DNA水平上研究基因调控机制 表观遗传学很少关注心脏转录组的转录后控制。我们到了 劫持高度保守的RNA结合蛋白-1(MBNL1)的功能 心肌细胞终末分化的转录重编程如何影响出生后发育和 梗死后再生和病理重塑。具体地说，该应用程序将使用一组增益和 允许心肌细胞特定时间剂量的MBNL1重新编程的功能丧失的小鼠模型 心脏的转录组实现以下目的：(1)确定MBNL1的作用依赖 转录组重编程在建立和维持心肌细胞分化中的作用，(2)定义 MBNL1依赖的转录组重编程在心肌梗死后再生和病理性心肌细胞中的作用 重塑，以及(3)确定MBNL1依赖的上下文依赖的调控机制 转录组重新编程。来自这些AIMS的数据将确定潜在的机制，通过 重编程可用于控制内源性或干细胞来源的心肌细胞的命运，作为一种新的 心脏重塑和再生的治疗策略。

Project Abstract Programmed terminal differentiation of cardiac myocytes is vital for reorganizing the heart's structure and function to meet basic physiologic demands. Many of these differentiation mechanisms are redeployed after ischemic injury or in the context of heart disease. While terminal differentiation is indispensable for basic cardiac function this fate change is associated with the nearly complete cessation of myocyte proliferation, which underlies one of the major barriers in the treatment of ischemic heart disease- the lack of effective therapeutic strategies to remuscularize the fibrotic heart. Many differentiation mechanisms are redeployed after injury, but it's unclear whether the response is adaptive or pathologic, thus understanding how the flow of genetic information establishes and maintains myocyte differentiation improves our current knowledge of basic cardiac physiology and provides insights into cardiac regeneration and disease. Much of our knowledge about terminal differentiation has come from investigating gene regulatory mechanisms at the level of DNA and epigenetics with little attention paid to post-transcriptional control of the cardiac transcriptome. Here we are hijacking the function of a highly conserved RNA-binding protein muscle blind like-1 (MBNL1) to understand how transcriptional reprogramming of myocyte terminal differentiation impacts post natal development and post-infarct regenerative and pathologic remodeling. Specifically, this application will use an array of gain and loss of function mouse models that permit cardiac myocyte specific temporal dosing of MBNL1 to reprogram the heart's transcriptome to achieve the following aims: (1) determine the role of MBNL1-dependent transcriptome reprogramming in establishing and maintaining cardiac myocyte differentiation, (2) define the role of MBNL1-dependent transcriptome reprogramming in post-infarct regenerative and pathologic myocyte remodeling, and (3) determine context dependent regulatory mechanisms underlying MBNL1-dependent transcriptome reprogramming. Data from these aims will identify potential mechanisms by which transcriptional reprogramming can be used to control either endogenous or stem-cell derived myocyte fate as a novel therapeutic strategy for cardiac remodeling and regeneration.