Regulatory Mechanisms of Endothelial Development and Regeneration

内皮发育和再生的调节机制

• 批准号: 9002076
• 负责人: Daniel J. Garry
• 金额: $ 38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9002076
• 关键词: Address; Adult; Biochemical; Biological; Blood; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Line; Cells; Congenital Abnormality; Congenital Cardiovascular Abnormality; Data; Daughter; Development; Disease; ES Cell Line; Embryo; Embryonic Development; Engineering; Feedback; Gene Expression; Genes; Genetic; Genetic Engineering; Genetic Models; Genetic Transcription; Goals; Health; Hematopoietic; Injury; Laboratories; Maps; MicroRNAs; Molecular; Morbidity - disease rate; Mus; Natural regeneration; Nucleic Acid Regulatory Sequences; Patients; Population; Publishing; Regenerative response; Regulation; Reporter Genes; Repression; Research; Role; Rosa; Smooth Muscle Myocytes; Societies; Stem cells; System; Techniques; Testing; Therapeutic; Time; Tissues; Trans-Activators; Transgenic Mice; Venus; Zebrafish; base; cardiovascular injury; clinically significant; in vivo; innovation; knock-down; knockin animal; malformation; mortality; mouse model; mutant; novel; overexpression; progenitor; programs; stem cell population

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.

描述（由申请人提供）：先天性心血管畸形是最常见的先天缺陷，并导致心血管患者的发病率和死亡率。该提案的远距离目标和临床意义是破译在内皮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的转录靶标，并证明ETV2调节了内膜/内皮谱系的分化。进一步的研究进一步确定了ETV2突变胚是不可行的，并且具有中胚层（内皮，造血和心脏）谱系的发育。基于我们的新结果，我们的总体假设是ETV2是开发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，我们将利用许多我们已经设计的新型遗传模型，并采用创新方法来剖析ETV2作为内皮祖细胞的调节剂的作用。为了检验我们的假设，我们将解决以下特定目的：特定目的＃1：定义胚胎发生过程中ETV2基因的调节；特定目的＃2：定义microRNA在内皮谱系的规范和区分方面的功能作用和特定的功能 目标＃3：定义在发育和再生过程中表达ETV2的细胞的细胞命运。这些目的将利用我们最近设计的遗传小鼠模型和ES细胞系全面定义ETV2作为必不可少的内皮调节剂的作用，并将作为治疗计划的前奏，以设计和再生脉管系统。鉴于心血管疾病在我们社会中的巨大发病率和死亡率，该提案的潜在影响很大。