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

基本信息

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
项目类别：
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

项目摘要

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功能，满足基本生理需求。许多这些分化机制在缺血性损伤或心脏病。而终端的分化对于基础的发展来说是不可或缺的。心脏功能这种命运的改变与心肌细胞增殖几乎完全停止有关，这是治疗缺血性心脏病的主要障碍之一——缺乏有效的治疗方法使纤维化心脏重新肌肉化的治疗策略。许多分化机制在损伤，但尚不清楚这种反应是适应性的还是病理性的，从而了解如何流动遗传信息建立并维持心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对心脏再生和疾病的见解。我们的很多知识都是关于终末分化来自于对 DNA 水平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。我们在这里劫持高度保守的RNA结合蛋白muscleblindlike-1（MBNL1）的功能来理解心肌细胞终末分化的转录重编程如何影响产后发育和梗塞后再生和病理重塑。具体来说，该应用程序将使用一系列增益和功能丧失小鼠模型允许心肌细胞特定时间给予 MBNL1 重新编程心脏的转录组要达到以下目的：（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依赖性转录组重编程在梗死后再生和病理性肌细胞中的作用重塑，以及（3）确定 MBNL1 依赖的背景依赖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作为一种新的方法可用于控制内源性或干细胞衍生的心肌细胞命运心脏重塑和再生的治疗策略。