FUNCTIONAL DISSECTIONS OF VEGF RECEPTORS IN ENDOTHELIUM

血管生成在许多重要的疾病过程和正常生理中起着关键作用。人们普遍预期，调节血管生成（抑制肿瘤，刺激血管功能不全）将提供重要的治疗效益。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因其效力，对血管内皮的选择性，以及在恶性肿瘤和其他血管生成发挥重要作用的临床条件下的一致过表达而脱颖而出。VPF/VEGF通过两种高亲和受体酪氨酸激酶Flt-1和KDR/Flk-1选择性作用于内皮细胞（EC）。这两种受体在发育和病理生理血管生成过程中通过EC表达水平升高。由于大多数内皮细胞同时表达这两种受体，并且它们与VPF/VEGF结合后都可以二聚体化，因此很难理解在同一配体存在下单个受体的分子功能。该研究旨在剖析这些受体在EC中VPF/VEGF介导的信号传导中的功能方面和唯一反应性。KDR和Flt-1及其各自突变体的嵌合受体将用于研究血管内皮细胞中KDR和Flt-1的信号通路。因此，该研究将描述这两种受体在VPF/ vegf介导的信号传导中的个体作用，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.