Transcriptional Control of Early Coronary Vascular Development

描述（由申请人提供）：血管异常和重塑发生在许多先天性和获得性疾病中，如心血管畸形、糖尿病、高血压、动脉和静脉的肺部疾病、外周血管疾病和心肌缺血和梗死。血管发育缺陷已被确定为胎儿死亡的主要原因。然而，有一个知识的基础上正常的血管发育的机制，特别是关于内皮细胞和血管平滑肌细胞的祖细胞和因子，决定他们的承诺，血管表型的知识很少。此外，这些前体随后进一步发展多样性的遗传机制还没有得到很好的理解。这些机制对于维持健康的血管系统和修复成熟生物体中的损伤可能是重要的。在哺乳动物中，冠状血管的发育依赖于心外膜内短暂的早期胚胎结构。心外膜内的细胞在心脏表面上迁移，形成心外膜和随后的心外膜下间充质细胞（SEMC）。SEMC对心脏发育的多个方面都很重要，并产生由成纤维细胞、内皮细胞和平滑肌细胞组成的整个冠状动脉血管系统。我们实验室最近的研究已经确定两种转录因子，血清反应因子（SRF）和GATA 4，在控制心外膜的发育中起着重要的作用。本申请的重点是确定这些因子之一SRF在调节心外膜前冠状动脉血管祖细胞向血管发育承诺所需的基因表达程序中的作用。我们将利用转基因SRF条件基因敲除动物，我们最近开发的，以解决的假设，最初SRF是需要形成的心外膜。这些研究的结果不仅将阐明控制早期冠状动脉血管发育的潜在转录调控机制，而且还将确定可能具有导致心脏再生治疗应用潜力的冠状动脉血管前体干细胞。

DESCRIPTION (provided by applicant): Vascular anomalies and remodeling occur in many congenital and acquired diseases such as cardiovascular malformations, diabetes, hypertension, pulmonary diseases of arteries and veins, peripheral vascular disease and myocardial ischemia and infarction. Defects in vascular development have been identified as a major cause of fetal demise. However, there is a paucity of knowledge of the mechanisms that underlie normal vascular development and particularly regarding the progenitors of endothelial and vascular smooth muscle cells and factors that determine their commitment to blood vessel phenotypes. Additionally, the genetic mechanisms by which these precursors subsequently develop further diversity are not well understood. These mechanisms are likely important for the maintenance of healthy vascular systems and for repair of damage in mature organisms. In mammals coronary vascular development is dependent on transient early embryonic structures within the proepicardium. Cells within the proepicardium migrate over the surface of the heart forming the epicardium and subsequently subepicardial mesenchymal cells (SEMC). SEMC are important for multiple aspects of heart development and give rise to the entire coronary vasculature consisting of fibroblasts, endothelial, and smooth muscle cells. Recent studies in our labs have determined that two transcription factors, Serum Response Factor (SRF) and GATA4, play seminal roles in controlling development of the proepicardium. The focus of this application is to determine the role of one of these factors, SRF, in regulating programs of gene expression required for commitment of proepicardial coronary vascular progenitor cells to vascular development. We will take advantage of transgenic SRF conditional gene knockout animals, recently developed by us, to address the hypothesis that initially SRF is required for formation of the proepicardium. The results of these studies will not only elucidate the underlying transcriptional regulatory mechanisms controlling early coronary vascular development, but should also identify coronary vascular precursor stem cells that may have the potential to lead to therapeutic applications in cardiac regeneration.