Integrating Transcriptome Reprogramming Into Cardiac Plasticity Regulatory Mechanisms

将转录组重编程整合到心脏可塑性调节机制中

• 批准号: 9902513
• 负责人: Jennifer Michelle Davis
• 金额: $ 42.67万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902513
• 关键词: Address; Adult; Attention; Binding; Biology; Birth; Brain; Cardiac; Cardiac Myocytes; Cardiac development; Cell Differentiation process; DNA; Data; Disease; Dose; Embryo; Epigenetic Process; Fibroblasts; Frequencies; Gene Transfer; Genes; Genetic Models; Genetic Transcription; Genomics; Growth; Heart; Heart Diseases; Infarction; Injury; Knock-out; Knowledge; Location; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Mediating; Mus; Muscle; Muscle Cells; Muscle Proteins; Muscular Atrophy; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocardium; Myotonic Dystrophy; Natural regeneration; Nodal; Pathologic; Pathway interactions; Phenotype; Physiological; Physiology; Positioning Attribute; Post-Transcriptional Regulation; Protein Biosynthesis; Proteins; RNA; RNA Processing; RNA Splicing; RNA-Binding Proteins; Regulation; Regulator Genes; Role; Specificity; Structure; Testing; Therapeutic; Tissues; Transcript; Transgenic Mice; Treatment Efficacy; Viral Genes; Workload; blind; cardiac regeneration; cardiac repair; cardiogenesis; cell behavior; crosslink; fetal; genetic information; genome-wide; heart function; improved; insight; ischemic injury; loss of function; mouse model; neonate; novel therapeutics; pluripotency; postnatal; postnatal development; recruit; regenerative; repaired; response; stem cells; transcriptome; transcriptomics; wound

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.

项目摘要 心肌细胞的程序性终末分化对于重组心脏结构和 满足基本的生理需求。这些分化机制中的许多在 缺血性损伤或在心脏病的情况下。虽然终端差异化是必不可少的基本 心脏功能这种命运变化与肌细胞增殖的几乎完全停止有关， 这是治疗缺血性心脏病的主要障碍之一-缺乏有效的 使纤维化心脏肌肉化的治疗策略。许多差异化机制在 损伤，但目前还不清楚这种反应是适应性的还是病理性的，从而了解细胞的流动是如何发生的。 遗传信息建立和维持肌细胞分化提高了我们目前的基本知识， 心脏生理学，并提供深入了解心脏再生和疾病。我们的大部分知识 终末分化来自于DNA水平上的基因调控机制的研究， 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结合蛋白肌盲样蛋白1（MBNL 1）的功能，以了解 肌细胞终末分化的转录重编程如何影响纳塔尔后发育， 梗死后再生和病理性重塑。具体来说，该应用程序将使用增益和 允许心肌细胞特异性时间给药MBNL 1以重编程的功能丧失小鼠模型 心脏的转录组，以实现以下目的：（1）确定MBNL 1依赖的作用， 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 MBNL 1依赖性转录组重编程在梗死后再生和病理性心肌细胞中的作用 重塑，和（3）确定MBNL 1依赖性的背景依赖性调节机制 转录组重编程来自这些目标的数据将确定转录的潜在机制 重编程可用于控制内源性或干细胞衍生的肌细胞命运，作为一种新的免疫调节方法。 心脏重塑和再生的治疗策略。