Embryonic Blood Vessel Formation

描述（由申请人提供）：本提案的研究重点是胚胎血管发育的分子和细胞机制。先前的研究已经证明，许多生长因子/信号分子在胚胎原始血管网络的形成过程中发挥重要作用。这些包括VEGF、血管生成素、特异性Notch途径组分以及某些肝配蛋白。以青蛙和鸡胚为模型系统，我们有初步的证据表明，两个额外的生长因子参与调控胚胎血管发生。首先，我们表明，刺猬家族蛋白的信号是至关重要的血管形成。其次，我们有证据表明，爱帕琳信号通过其G蛋白偶联受体，APJ，也是重要的血管系统的初始模式。该提案的两个具体目标旨在进一步探索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（成血管细胞）的起源。我们建议通过确定最终的成血管细胞标志物VEGFR-2（也称为ilk-1或KDR）的表达所需的转录因子来确定成血管细胞形成的可能调节因子。建议中实验的具体目的如下：（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。鉴定成血管细胞中VEGFR-2表达所必需的DNA调控元件，从而确定定义成血管细胞谱系所需的转录因子。 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。考虑到脊椎动物发育的基本机制的保守性，使用鸡和青蛙胚胎获得的结果极有可能直接适用于理解其他生物（包括人类）胚胎脉管系统的形成。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.