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: 8063951
• 负责人: Michael S Parmacek
• 金额: $ 49.82万
• 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/8063951
• 关键词: Ablation; Actins; Adherence; Adult; Animals; Aortic Diseases; Arteries; Atherosclerosis; Automobile Driving; Award; Biological; Biological Assay; Blood Vessels; Cardiac; Cardiac Myocytes; 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; 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; United States National Institutes of Health; 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; 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(申请人提供)：转录共激活子扩展编码在基因组中的信息，以响应发育线索和环境压力。Myocardin是一种非常有效的转录辅助激活因子，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证明，myocardin在调节血管SMCs的分化方面发挥着关键作用。这项研究的总体目标是阐明肌钙蛋白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。在本奖项的最后一个周期中，我们报道：i)myocardin、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)Myocardin、MRTF-A或MRTF-B在胚胎干细胞(ES)中的强制表达激活内源性SMC限制基因，iii)在神经棘来源的SMC中Myocardin基因被去除的小鼠由于SMC分化受阻而表现出动脉导管未闭(PDA)，iv)Myocardin缺陷的初级主动脉SMC呈现合成表型，和v)MRTF-B基因缺失的小鼠表现出心脏流出道和大动脉的图案性缺陷，部分原因是神经脊来源的SMC分化过程中的细胞自主阻断。总之，这些研究提出了将在拟议的研究中检验的中心假设：Myocardin相关转录因子(MRTF)转导SMC分化、血管构型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。其具体目的是检测：1)myocardin、MRTF-A和MRTF-B促进SMC分化和收缩的SMC表型的细胞自主功能(S)；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构型中的作用；3)myocardin基因缺失和条件突变小鼠，以阐明myocardin在胚胎血管生成及出生后血管系统的维持和适应中的功能。所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换为完整的血管系统。在基础水平上，这些研究将为调控血管系统的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，这些研究直接关系到了解血管增殖综合征、先天性心脏病和主动脉疾病的分子和遗传学基础。 公共卫生相关性：令人信服的证据表明，心肌钙蛋白相关转录因子(MRTF)在调节心血管系统的发育和维持心血管内稳态方面发挥着关键作用。这项拟议的研究考察了MRTF在胚胎和出生后发育过程中调节活性的分子机制。这些研究直接关系到对血管增生性综合征的了解，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。