REGULATION OF VASCULAR GROWTH AND DIFFERENTIATION

血管生长和分化的调节

• 批准号: 6102402
• 负责人: Patricia Ann D'Amore
• 金额: $ 20.9万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6102402
• 关键词: RNA splicing; RNase protection assay; angiogenesis; biological models; cell differentiation; cell growth regulation; cell proliferation; embryonic stem cell; gene expression; histogenesis; in situ hybridization; laboratory mouse; protein isoforms; vascular endothelial growth factors; vascular endothelium

The vasculature forms by a combination of vasculogenesis and angiogenesis. Convincing data indicate a role for vascular endothelial growth factor (VEGF) in both process. VEGF exists as three isoforms that arise by alternative splicing. Recent data suggest that the isoforms differ in their mitogenic potential but other functional differences have yet to be determined. In addition, the precise role and regulation of VEGF during vascular development are known. Finally, little is known about the molecules that maintain the adult vasculature in a differentiated, quiescent state. This proposal is founded on the hypothesis that specific molecules regulate vascular growth and differentiation. Our long-term objective is to identify these molecules and their functions. To accomplish this following aims are proposed. (1) To examine the expression and function of the VEGF isoforms during development in vivo. Isoform expression will be examined during mouse development using Rnase protection and in situ hybridization. Isoform function will be assessed by targeted exon deletion to generate mice expression specific VEGF isoforms. (2) To investigate the role and regulation of VEGF during vascular development. ES cells differentiated into embryoid bodies will be used as an in vitro model of vasculogenesis. The regulation of VEGF expression will be characterized in this model by studying the expression of stably transfected VEGF promoter/reporter constructs. VEGF isoform function will also be examined in this system. (3) To characterize the nature and function of a novel gene highly expressed by quiescent but not proliferating EC. This gene (frizzled) is homologous in C. elegans through humans. Expression studies in vivo and in vitro suggest the gene product may contribute to the regulation of endothelial growth and/or differentiation. Together the results of these investigations should add to our understanding of the mechanism (s) that regulate vascular growth and differentiation.

脉管系统通过脉管发生和 血管生成。 说服数据表明血管内皮的作用 两个过程中的生长因子（VEGF）。 VEGF作为三种同工型存在 这是通过替代剪接而产生的。 最近的数据表明 同工型的有丝分裂潜力不同，但其他功能 差异尚未确定。 另外，精确的角色 VEGF在血管发育过程中的调节是已知的。 最后，关于维持成人的分子知之甚少 脉管系统处于差异化状态。 该提议是 建立在特定分子调节血管的假设上 生长与分化。 我们的长期目标是确定这些 分子及其功能。 实现以下目标是 建议的。 （1）检查VEGF的表达和功能 在体内发育过程中的同工型。 同工型表达将是 使用RNase保护和在鼠标开发过程中检查 原位杂交。 同工型功能将通过靶向外显子评估 删除以产生小鼠表达特定VEGF同工型。 （2）至 研究VEGF在血管中的作用和调节 发展。 将使用分化为胚胎体的ES细胞 作为血管生成的体外模型。 VEGF的调节 通过研究 稳定转染的VEGF启动子/报告基因构建体的表达。 VEGF同工型功能也将在该系统中进行检查。 （3）到 表征高表达的新型基因的性质和功能 通过静止，但不扩散EC。 这个基因（卷曲）是 通过人类在秀丽隐杆线虫中同源。 体内表达研究 并在体外表明基因产物可能有助于调节 内皮生长和/或分化。 一起的结果 这些调查应该增加我们对机制的理解 （S）调节血管生长和分化。