Myocardin Related Transcription Factor Function in the Vasculature

脉管系统中心肌素相关转录因子的功能

• 批准号: 7906443
• 负责人: Michael S Parmacek
• 金额: $ 47.15万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-19 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7906443
• 关键词: Ablation; Actins; Adherence; Adult; Animals; Aortic Diseases; Arteries; Atherosclerosis; Automobile Driving; Award; Biological; Biological Assay; Blood Vessels; Cardiac; Cardiovascular system; Cell Differentiation process; Cell Lineage; Cell Nucleus; Cells; Cellular Morphology; Chemotaxis; Complement Factor B; Congenital Heart Defects; Cues; Data; Defect; Development; Embryo; Emigrations; Exhibits; Family; Genes; Genetic Transcription; Genetically Engineered Mouse; Genome; Goals; Harvest; Homeostasis; Knockout Mice; Maintenance; Maps; Mediating; Molecular; Molecular Genetics; Mus; Muscle Cells; Mutant Strains Mice; Mutation; Neural Crest; Neural Crest Cell; Neural tube; Patent Ductus Arteriosus; Pattern; Pericytes; Phenotype; Physiological; Play; Property; Reagent; Reporting; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Specificity; Stress; Syndrome; Transcription Coactivator; Translations; Undifferentiated; Vascular System; Yolk Sac; angiogenesis; base; cell motility; cellular transduction; chromatin immunoprecipitation; congenital heart disorder; embryonic stem cell; epithelial to mesenchymal transition; extracellular; factor A; insight; loss of function; migration; mouse model; myocardin; null mutation; postnatal; programs; public health relevance; response; rho; stem; transcription factor

DESCRIPTION (provided by applicant): Transcriptional co-activators expand information encoded within the genome in response to developmental cues and environmental stress. Myocardin is remarkably potent transcriptional coactivator expressed exclusively in smooth muscle cells (SMCs) and cardiac myocytes. Our group and others have shown that myocardin, plays a critical role in regulating differentiation of vascular SMCs. The overall goal of the proposed studies is to elucidate the role of myocardin and two related transcriptional co-activators, MRTF-A and MRTF-B, in the embryonic and adult vasculature. During the last cycle of this award, we reported that: i) myocardin, MRTF-A and MRTF-B are expressed in distinct developmentally-regulated patterns in mesodermally- and neural crest-derived SMCs, ii) forced expression of myocardin, MRTF-A or MRTF-B in embryonic stem (ES) cells activates endogenous SMC-restricted genes, iii) mice in which the myocardin gene is ablated in neural crest-derived SMCs exhibit patent ductus arteriosus (PDA) resulting from a block in SMC differentiation, iv) myocardin-deficient primary aortic SMCs assume a synthetic phenotype, and v) MRTF-B null mice exhibit patterning defects of the cardiac outflow tract and great arteries attributable, in part, to a cell autonomous block in differentiation of neural crest-derived SMCs. Together these studies suggest the central hypothesis that will be examined in the proposed studies: Myocardin related transcription factors (MRTFs) transduce cell autonomous and non-cell autonomous signals required for SMC differentiation, vascular patterning and maintenance and adaptation of the vasculature during postnatal development. The specific aims are to examine: 1) the cell autonomous function(s) of myocardin, MRTF-A and MRTF-B that promote SMC differentiation and the contractile SMC phenotype; 2) the role of MRTF-A and MRTF-B in differentiation of neural crest-derived SMCs and patterning of the cardiac outflow tract and great arteries; and 3) myocardin null and conditional mutant mice to elucidate the function of myocardin during embryonic angiogenesis and in maintenance and adaptation of the postnatal vasculature. The experimental strategies deployed emphasize the translation of molecular and cellular data to the intact vascular system utilizing genetically engineered mice. At a basic level, these studies will provide new insights into the molecular programs regulating smooth muscle cell differentiation and morphogenetic patterning of the vasculature. Moreover, these studies are directly relevant to understanding the molecular and genetic basis of vascular proliferative syndromes, congenital heart disease and diseases of the aorta. PUBLIC HEALTH RELEVANCE: Compelling evidence suggests that myocardin related transcription factors (MRTFs) play critical roles in regulating development of the cardiovascular system and maintenance of cardiovascular homeostasis. The proposed studies examine the molecular mechanisms regulating activity of MRTFs during embryonic and postnatal development. These studies are directly relevant to understanding vascular proliferative syndromes including atherosclerosis, common forms of congenital heart disease and aortic diseases.

描述（由申请人提供）：转录共激活因子扩展基因组内编码的信息，以响应发育线索和环境压力。肌心素是一种特异性表达于平滑肌细胞和心肌细胞的转录辅激活因子。我们的小组和其他人已经表明，心肌蛋白在调节血管平滑肌细胞的分化中起着关键作用。拟议的研究的总体目标是阐明myocardin和两个相关的转录共激活因子，MRTF-A和MRTF-B，在胚胎和成人血管系统中的作用。在该奖项的最后一个周期，我们报告说：i）心肌素、MRTF-A和MRTF-B在中胚层和神经嵴来源的SMC中以不同的发育调节模式表达，ii）心肌素、MRTF-A或MRTF-B在胚胎干（ES）细胞中的强制表达激活内源性SMC限制性基因，iii）在神经嵴来源的SMC中心肌素基因被消融的小鼠表现出由SMC分化阻断引起的动脉导管未闭（PDA），iv）肌心蛋白缺陷的原发性主动脉SMC呈现合成表型，和v）MRTF-B缺失小鼠表现出心脏流出道和大动脉的图案化缺陷，部分归因于神经嵴衍生的SMC分化中的细胞自主阻断。这些研究共同提出了将在拟议研究中检查的中心假设：心肌素相关转录因子（MRTFs）是SMC分化、血管图案形成以及出生后发育期间血管系统的维持和适应所需的细胞自主和非细胞自主信号。本研究的具体目的是：1）心肌素、MRTF-A和MRTF-B促进SMC分化和收缩SMC表型的细胞自主功能，2）MRTF-A和MRTF-B在神经嵴来源的SMC分化和心脏流出道和大动脉的模式中的作用;和3）心肌素无效和条件突变小鼠，以阐明心肌素在胚胎血管生成过程中以及在出生后脉管系统的维持和适应中的功能。部署的实验策略强调利用基因工程小鼠将分子和细胞数据转化为完整的血管系统。在基础水平上，这些研究将为调节血管平滑肌细胞分化和形态发生模式的分子程序提供新的见解。此外，这些研究与了解血管增生综合征、先天性心脏病和主动脉疾病的分子和遗传基础直接相关。 公共卫生相关性：心肌素相关转录因子（myocardin related transcription factors，MRTF）在调节心血管系统发育和维持心血管稳态中起着重要作用。拟议的研究探讨了在胚胎和出生后发育过程中调节MRTFs活性的分子机制。这些研究直接关系到了解血管增生综合征，包括动脉粥样硬化，常见形式的先天性心脏病和主动脉疾病。