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，并导致心血管患者的发病率和死亡率。该提议的长期目标和临床意义是破译在内皮发育和再生期间支配祖细胞的网络。我们的实验室发现Etv 2/Etsrp 71/ER 71作为Nkx 2 -5的转录靶点，并证明Etv 2调节内皮细胞/内皮谱系的分化。其他研究进一步确定了Etv 2突变胚胎是不能存活的，并且扰乱了中胚层（内皮、造血和心脏）谱系发育。基于我们的新结果，我们的总体假设是Etv 2是发育和再生过程中内皮谱系主分子程序的重要因素。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，并采取创新的方法来剖析Etv 2作为内皮祖细胞调节因子的作用。为了检验我们的假设，我们将提出以下具体目标：具体目标#1：确定胚胎发生过程中Etv 2基因的调控;具体目标#2：确定microRNA在内皮细胞谱系的特化和分化中的功能作用;具体目标#3：确定内皮细胞谱系的特化和分化中的功能作用。 目的#3：确定Etv 2表达细胞在发育和再生过程中的细胞命运。这些目标将利用我们最近工程化的遗传小鼠模型和ES细胞系来全面定义Etv 2作为重要内皮调节剂的作用，并将作为工程化和再生血管系统的治疗计划的前奏。鉴于我们社会中心血管疾病的发病率和死亡率非常高，该提案的潜在影响是巨大的。

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.