Regulatory Mechanisms of Endothelial Development and Regeneration

描述（由申请人提供）：先天性心血管畸形是最常见的出生缺陷，也是导致我们心血管患者发病率和死亡率的原因之一。这项研究的长期目标和临床意义是破译内皮细胞发育和再生过程中控制祖细胞的网络。我们的实验室发现Etv2/Etsrp71/ER71是Nkx2-5的转录靶点，并证明Etv2调节心内膜/内皮细胞谱系的分化。其他研究进一步确定，Etv2突变胚胎不能存活，并且中胚层（内皮、造血和心脏）谱系发育受到干扰。基于我们的新结果，我们的总体假设是，Etv2是内皮细胞在发育和再生过程中主要分子程序的一个重要因素。在这些拟议的研究中，我们将利用我们设计的一些新的遗传模型，并采用创新的方法来剖析Etv2作为内皮祖细胞调节剂的作用。为了检验我们的假设，我们将解决以下具体目标：具体目标#1：定义胚胎发生过程中Etv2基因的调控；特异性目标#2：定义microrna在内皮细胞谱系和特异性分化中的功能作用

DESCRIPTION (provided by applicant): Congenital cardiovascular malformations are the most common birth defect and contribute to the morbidity and mortality of our cardiovascular patients. The long range goal and the clinical significance of this proposal are to decipher the networks that govern the progenitors during endothelial development and regeneration. Our laboratory discovered Etv2/Etsrp71/ER71 as a transcriptional target of Nkx2-5 and demonstrated that Etv2 regulates the differentiation of endocardial/endothelial lineages. Additional studies further defined that Etv2 mutant embryos were nonviable and had perturbed mesodermal (endothelial, hematopoietic and cardiac) lineage development. Based on our novel results, our overall hypothesis is that Etv2 is an essential factor for the master molecular program for the endothelial lineage during development and regeneration. In these proposed studies, we will utilize a number of novel genetic models that we have engineered and take an innovative approach to dissect the role of Etv2 as a regulator of endothelial progenitors. To examine our hypotheses, we will address the following specific aims: Specific Aim #1: To define the regulation of the Etv2 gene during embryogenesis; Specific Aim #2: To define the functional role of microRNAs for the specification and differentiation of the endothelial lineage and Specific Aim #3: To define the cell fate of the Etv2 expressing cells during development and regeneration. These aims will utilize our recently engineered genetic mouse models and ES cell lines to comprehensively define the role for Etv2 as an essential endothelial regulator and will serve as prelude for therapeutic initiatives to engineer and regenerate the vasculature. Given the tremendous morbidity and mortality of cardiovascular disease in our society, the potential impact of this proposal is significant.