Embryonic Blood Vessel Formation

描述(由申请人提供)：本提案中的研究重点是胚胎血管发育的分子和细胞机制。先前的研究表明，一些生长因子/信号分子在胚胎原始血管网络的形成过程中发挥着至关重要的作用。这些物质包括血管内皮生长因子、血管生成素、特定的Notch途径成分以及某些肾上腺素。以青蛙胚胎和鸡胚胎为模型系统，我们有初步证据表明，另外两个生长因子参与了胚胎血管生成的调节。首先，我们证明了Hedgehog家族蛋白的信号转导在血管形成中是必不可少的。其次，我们有证据表明，通过其G蛋白偶联受体APJ传递的apelin信号对血管系统的初始模式也很重要。该提案的两个具体目标旨在进一步探讨这些信号通路在血管发育中的作用。最后，我们正在研究胚胎中原始血管内皮前体细胞(血管母细胞)的来源。我们建议通过确定血管母细胞标志物VEGFR-2(也称为ILK-1或KDR)的表达需要哪些转录因子来确定血管母细胞形成的可能调控因素。方案中实验的具体目标如下：(1)。为了进一步研究Hedgehog信号在血管发育中的作用，2)探讨apelin信号在血管发育中的作用，(3)鉴定血管母细胞中VEGFR-2表达所必需的DNA调控元件，从而确定哪些转录因子是确定血管母细胞谱系所必需的。 我们研究的长期目标是了解胚胎血管组织形成和发育的分子机制。鉴于脊椎动物发育的基本机制的保守性，利用鸡和青蛙胚胎获得的结果极有可能直接适用于理解包括人类在内的其他生物的胚胎血管系统的形成。这项研究具有广泛的意义，因为胚胎血管发育的基本机制可能在与肿瘤发生、伤口愈合和血管修复相关的血管形成过程中得到重申。

DESCRIPTION (provided by applicant): Research in this proposal focuses on the molecular and cellular mechanisms underlying embryonic vascular development. Previous studies have demonstrated that a number of growth factor/signaling molecules play essential roles during formation of the original blood vessel network in the embryo. These include VEGF, angiopoietin, specific Notch pathway components and also certain ephrins. Using the frog and chick embryos as model systems, we have preliminary evidence showing that two additional growth factors are involved in regulation of embryonic vasculogenesis. First, we show that signaling by hedgehog family proteins is essential for vascular tube formation. Second, we have evidence suggesting that apelin signaling through its G-protein coupled receptor, APJ, is also important for initial patterning of the vascular system. Two of the specific aims of this proposal are designed to further explore the role of these signaling pathways in vascular development. Finally, we are investigating the origin of the original vascular endothelial precursor cells (angioblasts) in the embryo. We propose to identify possible regulators of angioblast formation, by determining which transcription factors are required for expression of the definitive angioblast marker VEGFR-2 (also called ilk-1 or KDR). The specific aims of the experiments in the proposal are as follows; (1). To further characterize the function of hedgehog signaling in vascular development, 2) To explore the role of apelin signaling during vascular development, (3). To identify DNA regulatory elements essential for VEGFR-2 expression in angioblasts and thereby to determine which transcription factors are required for defining the angioblast lineage. The long term goal of our research is to understand the molecular mechanisms underlying patterning and development of embryonic vascular tissues. Given the conservation of basic mechanisms underlying vertebrate development, it is extremely likely that results obtained using chick and frog embryos will be directly applicable to understanding formation of the embryonic vasculature in other organisms, including humans. This research has broad significance because the basic mechanisms underlying embryonic vascular development are likely to be reiterated during blood vessel formation associated with tumorogenesis, wound healing and vascular repair.