Molecular Regulation of Vascular Development

描述（由申请人提供）：我们的目标是了解控制血管发生和血管生成的分子机制。在这些过程中最重要的是排列在所有血管腔内的内皮细胞，它们在血管系统的形成、重塑和正常生理功能中起着关键作用。此外，内皮细胞还参与血管形成的功能失调或病理过程，如动脉粥样硬化、伤口愈合、类风湿关节炎和牛皮癣。在对小鼠胚胎干细胞和胚胎早期循环系统基因的基因筛选中，我们发现了新的锌指基因——血管内皮锌指1 （Vascular endothelial zinc finger 1, Vezfl）。VEZF1是一种56 KD的锌指转录因子，以序列特异性的方式结合IL-3启动子中的CT/GC-rich区域以及内皮特异性基因的几个启动子。其在胚胎发生过程中的表达仅限于卵黄囊血岛中的血管内皮细胞及其中胚层前体。在成人中，Vezfl在毛细血管和成熟血管的内皮中表达水平降低。它也在骨髓巨核细胞中表达。Vezfl在动脉损伤和肿瘤血管生成过程中被诱导。鉴于其受限的表达模式，我们假设Vezfl在血管内皮谱系的确定和/或分化过程中调节分子过程。为了支持我们的假设，包括小鼠胚胎中Vezfl的功能缺失和功能获得突变在内的分子遗传学方法表明，Vezfl以剂量依赖的方式起作用，并且是血管系统正常增殖、重塑和完整性所必需的。为了更好地了解Vezfl在血管发育中的作用，我们建议详细研究Vezfl如何参与控制血管形成的分子途径。我们将识别和表征Vezfl基因中内皮细胞和巨核细胞特异性表达所必需和充分的调控区域。我们将分离和表征与这些调控区域功能相互作用的蛋白质。最后，我们将确定受VEZF1调控的候选靶基因。

DESCRIPTION (provided by applicant): Our goal is to understand the molecular mechanisms that govern vasculogenesis and angiogenesis. Of primary importance in these processes are the endothelial cells that line the lumen of all blood vessels, playing a key role in the formation, remodeling, and normal physiological function of the vascular system. In addition, endothelial cells are involved in dysfunctional or pathological processes of vessel formation, such as atherosclerosis, wound healing, rheumatoid arthritis and psoriasis. In a genetic screen for early circulatory system genes in mouse embryonic stem (ES) cells and embryos, we identified the novel zinc finger gene, Vascular endothelial zinc finger 1 (Vezfl). VEZF1 is a 56 KD zinc finger transcription factor that binds in a sequence-specific manner to CT/GC-rich regions in the IL-3 promoter as well as in several promoters from endothelial-specific genes. Its expression during embryogenesis is restricted to vascular endothelial cells and their mesodermal precursors in the yolk sac blood islands. In adults, Vezfl is expressed at reduced levels in the endothelium of the capillaries and mature vessels. It is also expressed in bone marrow megakaryocytes. Vezfl is induced during arterial injury and tumor angiogenesis. In light of its restricted pattern of expression we hypothesize that Vezfl regulates molecular processes during the determination and/or differentiation of the vascular endothelial lineage. In support of our hypothesis, molecular genetic approaches including loss- and gain-of-function mutations of Vezfl in mouse embryos indicate that Vezfl acts in a dosage-dependent manner and is required for the normal proliferation, remodeling, and integrity of the vasculature. To better understand the role of Vezfl during vascular development, we propose to study in detail how Vezfl participates in the molecular pathways that control blood vessel formation. We will identify and characterize regulatory regions within the Vezfl gene that are required and sufficient for endothelial, and megakaryocyte specific expression. We will isolate and characterize proteins that functionally interact with these regulatory regions. Finally, we will identify candidate target genes that are regulated by VEZF1.