FUNCTIONAL DISSECTIONS OF VEGF RECEPTORS IN ENDOTHELIUM

血管生成在许多重要的疾病过程中起着关键作用，在正常生理中也是如此。人们普遍预期，调节血管生成(抑制肿瘤、刺激血管功能不全)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因其对血管内皮细胞的活性和选择性，以及在恶性肿瘤和其他临床条件下血管生成起重要作用的持续过表达而脱颖而出。VPF/VEGF通过两个高亲和力受体酪氨酸激酶Flt-1和KDR/Flk-1选择性(但非排他性)作用于内皮细胞(EC)。在发育和病理生理血管生成过程中，这两种受体的表达水平均由EC升高。由于大多数内皮细胞都表达这两种受体，而且两者都能与VPF/VEGF结合后发生同源二聚化，因此很难在同一配体存在的情况下理解单个受体的分子功能。本研究旨在分析这些受体在血管内皮生长因子/血管内皮细胞生长因子介导的信号转导中的功能特点和唯一的反应性。KDR和Flt-1的嵌合受体及其各自的突变体将被用于研究血管内皮细胞中负责KDR和Flt-1的信号通路。因此，这项拟议的研究将阐明这两种受体在VPF/VEGF介导的信号转导中的单独作用，并将为血管生成的分子机制提供新的线索。

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.