Regulatory Mechanisms of Endothelial Development and Regeneration

内皮发育和再生的调节机制

• 批准号: 8827844
• 负责人: Daniel J. Garry
• 金额: $ 37.43万
• 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/8827844
• 关键词: Address; Adult; Biochemical; Biological; Blood; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Line; Cells; Congenital 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; 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出生缺陷，导致心血管患者的发病率和死亡率增加。该提案的长期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。我们实验室发现Etv2/Etsrp71/ER71作为Nkx2-5的转录靶标，并证明Etv2调节心内膜/内皮谱系的分化。其他研究进一步明确，Etv2 突变体胚胎无法存活，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 Etv2 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许多新颖的遗传模型，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 Etv2 基因在胚胎发生过程中的调控；具体目标#2：定义 microRNA 对内皮谱系和特异性的规范和分化的功能作用 目标#3：确定 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基因小鼠模型和 ES 细胞系来全面定义 Etv2 作为重要内皮调节剂的作用，并将作为工程和再生脉管系统的治疗举措的前奏。鉴于我们社会中心血管疾病的巨大发病率和死亡率，该提案的潜在影响是巨大的。