Regulatory Mechanisms of Endothelial Development and Regeneration

描述(申请人提供)：先天性心血管畸形是最常见的出生缺陷，并导致我们的心血管病人的发病率和死亡率。这项提议的长期目标和临床意义是破译在内皮细胞发育和再生过程中管理祖细胞的网络。我们实验室发现ETV2/Etsrp71/ER71是Nkx2-5的转录靶点，并证实ETV2调控心内膜/内皮细胞系的分化。更多的研究进一步明确了ETV2突变胚胎是不能存活的，并且干扰了中胚层(内皮、造血和心脏)谱系的发育。根据我们的新结果，我们的总体假设是ETV2是内皮细胞在发育和再生过程中的主要分子程序的关键因素。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ETV2作为内皮祖细胞调节因子的作用。为了检验我们的假设，我们将解决以下特定目标：特定目标1：定义胚胎发育过程中ETV2基因的调节；特定目标2：定义microRNAs对内皮细胞谱系和特定细胞系的指定和分化的功能作用。 目的#3：明确ETV2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设计的遗传小鼠模型和ES细胞系来全面确定ETV2作为重要的内皮调节因子的作用，并将作为治疗倡议的前奏，以设计和再生血管系统。鉴于心血管疾病在我们的社会中的巨大发病率和死亡率，这项提议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.