Molecular Basis of Myocardin Function in the Heart

心脏心肌素功能的分子基础

基本信息

批准号：
7565445
负责人：
Michael S Parmacek
金额：
$ 42.82万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7565445
关键词：
Ablation Adult Biological Biological Assay Biomechanics Blood Vessels Boxing Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular system Cell Differentiation process Cell Nucleus Cell Proliferation Cells Complement Factor B Data Development Dominant-Negative Mutation Embryo Embryonic Heart Exhibits Feedback Gene Activation Gene Expression Gene Proteins Gene Targeting Genes Genetic Genetic Transcription Genetically Engineered Mouse Genome Goals Growth Heart Heart failure Hypertrophic Cardiomyopathy Hypertrophy Knock-in Mouse Maps Mediating Modeling Molecular Morphology Mus Muscle Cells Mutation Pathogenesis Pattern Phenotype Phosphorylation Physiological Plasmids Play Population Post-Translational Protein Processing Property Protein Isoforms Reagent Reporting Role Serum Response Factor Signal Pathway Signal Transduction Smooth Muscle Myocytes Specificity Stem cells Stimulus Stress Testing Transcription Coactivator Transcriptional Activation Transgenic Organisms Translations Undifferentiated Validation base cardiogenesis chromatin immunoprecipitation embryonic stem cell extracellular factor A feeding fetal hemodynamics in vivo insight myocardin null mutation postnatal progenitor programs protein expression public health relevance recombinase response transcription factor

Ablation Adult Biological Biological Assay Biomechanics Blood Vessels Boxing Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular system Cell Differentiation process Cell Nucleus Cell Proliferation Cells Complement Factor B Data Development Dominant-Negative Mutation Embryo Embryonic Heart Exhibits Feedback Gene Activation Gene Expression Gene Proteins Gene Targeting Genes Genetic Genetic Transcription Genetically Engineered Mouse Genome Goals Growth Heart Heart failure Hypertrophic Cardiomyopathy Hypertrophy Knock-in Mouse Maps Mediating Modeling Molecular Morphology Mus Muscle Cells Mutation Pathogenesis Pattern Phenotype Phosphorylation Physiological Plasmids Play Population Post-Translational Protein Processing Property Protein Isoforms Reagent Reporting Role Serum Response Factor Signal Pathway Signal Transduction Smooth Muscle Myocytes Specificity Stem cells Stimulus Stress Testing Transcription Coactivator Transcriptional Activation Transgenic Organisms Translations Undifferentiated Validation base cardiogenesis chromatin immunoprecipitation embryonic stem cell extracellular factor A feeding fetal hemodynamics in vivo insight myocardin null mutation postnatal progenitor programs protein expression public health relevance recombinase response transcription factor

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项目摘要

DESCRIPTION (provided by applicant): Transcriptional co-activators expand information encoded within the genome required for adaptation to environmental perturbation and stress. Myocardin is a remarkably potent transcriptional expressed exclusively in the heart and smooth muscle cells (SMCs). We have used transgenic and gene targeting strategies in mice to elucidate the molecular mechanisms that regulate heart and vascular development. Preliminary studies reveal that: i) myocardin is expressed in a precise developmentally regulated pattern in cardiomyocytes and SMCs, ii) forced expression of myocardin in embryonic stem cells activates cardiac-restricted genes associated with the hypertrophic gene program, iii) myocardin and MRTF-A activate overlapping, but distinct, sets of genes and most importantly iv) mice harboring a cardiac-specific conditional ablation of the myocardin gene exhibit hypertrophic cardiomyopathy. Together these studies suggest the central hypothesis that will be examined in the proposed studies: myocardin functions as a central regulator of cardiomyocyte growth and adaptation to stress via both feed-forward mechanisms, including activation of genes associated with the fetal /hypertrophic gene program, and feedback mechanisms regulating cell proliferation. The overall goal of this proposal is to elucidate the role of myocardin in the heart with particular focus on defining its function in cardiac myocyte differentiation and adaptation of the heart. The specific aims are to characterize: 1) the SRF- and MEF2-dependent transcriptional and morphogenetic programs regulated by myocardin in the heart, 2) mechanisms that distinguish activity and specificity of myocardin, MRTF-A and MRTF-B in the heart, and 3) molecular mechanisms modulating myocardin-dependent transcriptional activation in the adult heart and response to hypertrophic stimuli. The experimental strategy deployed emphasizes the translation and validation of molecular and cellular data in genetically engineered mice. At a basic level these studies will provide new insights into the transcriptional programs regulating cardiac myocyte differentiation and morphogenetic development of the heart. These studies also provide insights into the molecular mechanisms regulating adaptation of the heart to stress and the pathogenesis of cardiomyopathy. PUBLIC HEALTH RELEVANCE: This application will investigate how the transcriptional coactivator, Myocardin, regulates the differentiated state of the heart and the capacity of the heart to respond to hemodynamic stress. We have generated genetically altered mice with cardiac-restricted ablation of the Myocardin gene. Analysis of these mice will permit us to determine if myocardin controls the early differentiation of cardiac myocytes, as well as their role in re-programming gene expression in the adult heart when it is subjected to stress. These studies will provide new understanding into cardiac development as well as the underlying causes of heart failure and cardiomyopathy.

描述（由申请人提供）：转录共激活器扩展了适应环境扰动和压力所需的基因组中编码的信息。心肌素是一种非常有效的转录，仅在心脏和平滑肌细胞（SMC）中表达。我们已经在小鼠中使用了转基因和基因靶向策略来阐明调节心脏和血管发育的分子机制。初步研究表明：i）心肌在心肌细胞和SMC中以精确的发育调节模式表达，ii）在胚胎干细胞中强迫肌动蛋白在胚胎干细胞中激活了与肥大基因程序相关的心脏限制基因，III和MRTF-A活化的基因，但属于MIRTF-A的基因，但属于MIRTF-A的属性，最重要的是属于属性的概念，最重要的是概念的概念，最重要的是属于基因的基因。心肌基因的心脏特异性有条件消融表现出肥大性心肌病。这些研究共同提出了将在拟议的研究中进行研究的中心假设：心肌素作为心肌细胞生长的中心调节剂，并通过两种喂养前馈机制适应压力，包括激活与胎儿 /肥大基因程序相关的基因，以及调节细胞扩散的反馈机制。该提案的总体目标是阐明心肌在心脏中的作用，尤其着重于定义其在心肌细胞分化和心脏适应中的功能。具体目的是表征：1）肌动蛋白在心脏中调节的SRF-和MEF2依赖性转录和形态发生程序，2）在心脏中区分肌心脏机制和3）分子机制在成人心脏依赖性的触发性转移中，从而区分心脏中肌心脏机制的运动和特异性。部署的实验策略强调了基因工程小鼠中分子和细胞数据的翻译和验证。在基本层面上，这些研究将为调节心脏心肌分化和心脏形态发生发展的转录程序提供新的见解。这些研究还提供了对调节心脏适应压力和心肌病发病机制的分子机制的见解。公共卫生相关性：该应用将调查转录共激活剂Mycardin如何调节心脏的差异化状态和心脏能够应对血液动力学压力的能力。我们已经产生了遗传改变的小鼠，并用心脏限制的心肌蛋白基因消融。对这些小鼠的分析将使我们能够确定心肌素是否控制心肌细胞的早期分化，以及它们在受到压力时在成年心脏中重新编程基因表达中的作用。这些研究将为心脏发展以及心力衰竭和心肌病的根本原因提供新的理解。