Distinct pathways of VPF/VEGF receptors

描述（由申请人提供）：血管生成在 几种重要的疾病过程以及正常生理学。是 广泛预期血管生成的调节（肿瘤中的抑制， 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，这些VEGF-A脱颖而出，因为它的效力，选择性， 血管内皮及其在恶性肿瘤中的一致性过度表达 以及在其中血管生成起重要作用的其它临床病症中。 VEGF-A通过以下方式选择性地（但不是排他地）作用于内皮细胞（EC）： 两种高亲和力受体酪氨酸激酶Flt-1（VEGFR-1）和 KDR/Flk-1（VEGFR 22）这两种受体的表达水平都随着时间的推移而增加。 在发育和病理生理血管生成过程中的BC。因为，大多数 内皮细胞表达这两种受体， 在与VEGF-A结合时发生同源二聚化;因此难以理解 单个受体的分子功能在相同的存在下， 配体。拟议的研究旨在剖析功能方面和鞋底 这些受体对EC中VEGF-A介导的信号传导的反应性。嵌合 将利用VEGFR-1和VEGFR-2的受体及其各自的突变体 来研究负责单个受体的信号通路， 血管内皮细胞目的1将致力于揭示其分子功能 并剖析了增殖与迁移通道的信号通路 通过VEGFR-2。我们还将定义负责 内皮细胞发芽及其后续信号通路。在目标2中， 将研究VEGFR-1在内皮细胞中的功能方面， 执行。此外，检测VEGFR-1对细胞增殖的抑制作用， VEGFR-2功能和抑制所必需的途径也将被研究。 演示。此外，将测试VEGFR- 1是否具有任何 与神经纤毛蛋白-1的功能关系，一种未知的新的VEGF-A受体 特别是在移民方面。在目标3中，目标1和2的数据 将用于评估正常与 肿瘤诱导的血管生成。将使用一种新的蛋白质递送系统，或 将进行逆转录病毒介导的遗传操作， 在正常以及肿瘤诱导血管生成中靶分子。通过 靶向正常和肿瘤诱导的相同信号传导组分， 血管生成，我们将得到一个更好的图片，并作出更好的比较， 这两个事件。因此，拟议的研究将界定个人的作用， 受体在VEGF-A介导的信号传导，也将揭示新的光在 血管生成的分子机制。综合这些实验， 有可能确定新的治疗靶点，以对抗血管生成， 肿瘤和其他疾病过程中。

DESCRIPTION (Provided by applicant): Angiogenesis plays a pivotal role in several 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 VEGF-A stands out because of its potency, selectivity for vascular endothelium, and its consistent over expression in malignant tumors and in other clinical conditions in which angiogenesis plays an important role. VEGF-A acts selectively (though not exclusively) on endothelial cells (EC) by means of two high affinity receptor tyrosine kinases Flt-1(VEGFR-1) and KDR/Flk-1(VEGFR22) Both of these receptors are expressed at increased levels by BC 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 VEGF-A; 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 VEGF-A mediated signaling in EC. Chimeric receptors of both VEGFR-1 and -2 and their respective mutants will be utilized to study signaling pathways responsible for the individual receptors in vascular endothelial cells. Aim 1 will focus to reveal the molecular function and dissect the signaling pathways for proliferation vs. migration channeling through VEGFR-2. We will also define the receptor(s) responsible for endothelial cell sprouting and its subsequent signaling pathways. In Aim 2, investigation of the functional aspects of VEGFR-1 in endothelial cells will be performed. Furthermore, examination of inhibitory role of the VEGFR-1 for the VEGFR-2 function(s) and the pathways necessary for the inhibition will also be demonstrated. In addition, it will be tested whether VEGFR- 1 has any functional relationship with neuropilin-1, a new VEGF-A receptor of unknown function, particularly in EC migration. In Aim 3, the data from Aims 1 and 2 will be utilized to evaluate the signaling pathways between normal vs. tumor-induced angiogenesis. A novel protein delivery system will be utilized or retroviral mediated genetic manipulation will be carried out to inactivate the target molecule(s) in normal as well as tumor-induced angiogenesis. By targeting the same signaling components in normal as well as tumor-induced angiogenesis, we will get a better picture and make a better comparison between these two events. The proposed study thus will delineate the individual role of the receptors in VEGF-A-mediated signaling and will also shed new light on the molecular mechanisms of angiogenesis. Taken together these experiments are likely to identify new therapeutic targets in order to combat angiogenesis in tumors and also in other disease processes.