Myocardin Related Transcription Factor Function in the Vasculature

描述（由申请人提供）：转录共激活子扩展基因组内编码的信息，以响应发育线索和环境压力。心肌素是一种非常有效的转录共激活因子，仅在平滑肌细胞和心肌细胞中表达。我们的团队和其他人已经表明，心肌素在调节血管SMCs的分化中起着关键作用。这些研究的总体目标是阐明心肌素和两种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。在本奖项的最后一个周期中，我们报告说：i)在中胚层和神经嵴来源的SMCs中，心肌素、MRTF-A和MRTF-B以不同的发育调节模式表达；ii)胚胎干（ES）细胞中，心肌素、MRTF-A或MRTF-B的强制表达激活内源性SMC限制基因；iii)神经嵴来源的SMCs中，心肌素基因被切除的小鼠表现出动脉导管未闭（PDA），导致SMC分化受阻。iv)心肌素缺乏的原发性主动脉SMCs具有合成表型，v) MRTF-B缺失的小鼠表现出心脏流出道和大动脉的模式缺陷，部分归因于神经嵴来源的SMCs分化中的细胞自主阻滞。综上所述，这些研究提出了一个中心假设，将在拟议的研究中进行检验：心肌素相关转录因子（MRTFs）转导细胞自主和非细胞自主信号，这些信号是出生后发育过程中SMC分化、血管模式和血管系统的维持和适应所必需的。具体目的是研究：1)心肌素、MRTF-A和MRTF-B促进SMC分化和收缩性SMC表型的细胞自主功能；2) MRTF-A和MRTF-B在神经嵴源性SMCs分化及心流出道和大动脉模式中的作用；3)通过心肌素缺失和条件突变小鼠研究心肌素在胚胎血管生成和出生后血管系统维持和适应中的作用。采用的实验策略强调将分子和细胞数据转化为利用基因工程小鼠的完整血管系统。在基础水平上，这些研究将为平滑肌细胞分化和脉管系统形态发生模式的分子调控程序提供新的见解。此外，这些研究对了解血管增殖性综合征、先天性心脏病和主动脉疾病的分子和遗传基础有直接关系。

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.