FUNCTIONAL DISSECTIONS OF VEGF RECEPTORS IN ENDOTHELIUM

血管生成在许多重要的疾病过程中以及在正常生理中起着关键作用。 广泛预期血管生成的调节（肿瘤中的抑制、血管功能不全中的刺激）将提供重要的治疗益处。 许多不同的细胞因子和生长因子表达血管生成活性，其中VPF/VEGF由于其效力、对血管内皮的选择性以及其在恶性肿瘤和其中血管生成起重要作用的其他临床病症中的一致过表达而突出。 VPF/VEGF通过两种高亲和力受体酪氨酸激酶Flt-1和KDR/Flk-1选择性地（但不是唯一地）作用于内皮细胞（EC）。 这两种受体在发育过程中和病理生理性血管生成中由EC以增加的水平表达。 由于大多数内皮细胞表达这两种受体，并且它们在与VPF/VEGF结合时都可以同源二聚化，因此难以理解在相同配体存在下单个受体的分子功能。 拟议的研究旨在解剖这些受体的功能方面和唯一的反应VPF/VEGF介导的信号在EC。 KDR和Flt-1的嵌合受体及其各自的突变体将用于研究血管内皮细胞中负责KDR和Flt-1的信号通路。 因此，拟议的研究将描绘这两种受体在VPF/VEGF介导的信号传导中的个体作用，也将揭示血管生成的分子机制。

Angiogenesis plays a pivotal role in many important disease processes as well as in normal physiology. It is widely anticipated that modulation of angiogenesis (inhibition in tumors, stimulation in vascular insufficiency) will provide important therapeutic benefit. Many different cytokines and growth factors express angiogenic activity, of these VPF/VEGF stands out because of its potency, selectivity for vascular endothelium, and its consistent overexpression in malignant tumors and in other clinical conditions in which angiogenesis plays an important role. VPF/VEGF acts selectively (though not exclusively) on endothelial cells (EC) by means of two high affinity receptor tyrosine kinases Flt-1 and KDR/Flk-1. Both of these receptors are expressed at increased levels by EC during development and in pathophysiological angiogenesis. Since, most of the endothelial cells express both of the receptors and both of them can homodimerize upon binding to VPF/VEGF, therefore it is difficult to comprehend the molecular function of the individual receptor in the presence of the same ligand. The proposed study aims to dissect the functional aspects and sole responsiveness of these receptors for VPF/VEGF mediated signaling in EC. Chimeric receptors of both KDR and Flt-1 and their respective mutants will be utilized to study signaling pathways responsible for KDR and Flt-1 in vascular endothelial cells. The proposed study thus will delineate the individual role of these two receptors in VPF/VEGF-mediated signaling and will also shed new light on the molecular mechanisms of angiogenesis.