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

基本信息

批准号：
8444315
负责人：
Michael S Parmacek
金额：
$ 38.55万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-19 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444315
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

项目摘要

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.

描述（由申请人提供）：转录共激活因子扩展了基因组内编码的信息，以响应发育线索和环境压力。心肌素是在平滑肌细胞（SMC）和心肌细胞中仅表达的非常有效的转录共激活剂。我们的小组和其他人表明，心肌素在调节血管SMC的区分方面起着至关重要的作用。拟议研究的总体目标是阐明在胚胎和成人脉管系统中，肌无力和两个相关的转录共激活剂MRTF-A和MRTF-B的作用。 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神经rest衍生的SMC。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：肌动蛋白相关的转录因子（MRTFS）转导细胞自主和非细胞自主信号，用于SMC分化，血管模式，维持以及在产后发育过程中血管的适应性。具体目的是检查：1）促进SMC分化和收缩性SMC表型的肌动蛋白，MRTF-A和MRTF-B的细胞自主功能； 2）MRTF-A和MRTF-B在分化神经rest衍生的SMC以及心脏流出道和大动脉的作用； 3）心肌无效和条件突变小鼠，以阐明在胚胎血管生成期间以及在产后脉管系统的维持和适应过程中的心肌功能。部署的实验策略强调了利用基因工程小鼠的分子和细胞数据向完整的血管系统的翻译。在基本水平上，这些研究将为调节平滑肌细胞分化和脉管系统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殖综合征，先天性心脏病和主动脉疾病的分子和遗传基础直接相关。