Distinct pathways of VPF/VEGF receptors

VPF/VEGF 受体的不同通路

• 批准号: 6868040
• 负责人: DEBABRATA MUKHOPADHYAY
• 金额: $ 29.5万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6868040
• 关键词: angiogenesis; biological signal transduction; cell cycle; cell migration; cell proliferation; chimeric proteins; focal adhesion kinase; gene delivery system; genetic manipulation; growth factor receptors; growth inhibitors; laboratory mouse; laboratory rat; ligands; mutant; neurons; protein structure function; receptor binding; receptor expression; tissue /cell culture; transfection /expression vector; tyrosine analog; vascular endothelial growth factors; vascular endothelium

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.

描述(申请人提供)：血管生成在 一些重要的疾病过程以及正常的生理过程。它是 人们普遍预计，血管生成的调节(肿瘤中的抑制， 血管功能不全的刺激)将提供重要的治疗 利益。许多不同的细胞因子和生长因子表达血管生成 在这些血管内皮生长因子-A中，活性突出是因为它的效力，选择性 血管内皮细胞及其在恶性肿瘤中的一致过表达 在其他临床条件下，血管生成起着重要作用。 血管内皮生长因子-A通过以下途径选择性(但非排他性)作用于内皮细胞(EC) 两个高亲和力受体酪氨酸激酶Flt-1(VEGFR-1)和 KDR/Flk-1(VEGFR22)这两种受体在 BC在发育和病理生理血管生成中起重要作用。因为，大多数人 内皮细胞同时表达这两种受体，并且它们都可以 在与血管内皮生长因子-A结合时均二聚体；因此很难理解 单个受体在其存在时的分子功能 莱兰德。拟议的研究旨在剖析功能方面和唯一的 这些受体对血管内皮生长因子-A介导的信号在EC中的反应性。嵌合体 将利用VEGFR-1和VEGFR-2的受体及其各自的突变体 为了研究负责单个受体的信号通路 血管内皮细胞。目标1将重点揭示分子功能 并剖析了增殖与迁移通道的信号通路 通过VEGFR-2。我们还将定义负责的受体(S) 内皮细胞萌发及其后续的信号通路。在目标2中， VEGFR-1在内皮细胞中的功能方面的研究将是 已执行。此外，检测VEGFR-1对血管内皮细胞生长的抑制作用 血管内皮生长因子受体-2的功能(S)和抑制所需的途径也将是 演示了。此外，还将测试VEGFR-1是否有 一种未知的新血管内皮生长因子-A受体与神经粘连蛋白-1的功能关系 功能，特别是在欧共体迁移过程中。在目标3中，来自目标1和目标2的数据 将被用来评估正常和 肿瘤诱导的血管生成。一种新的蛋白质输送系统将被利用或 将进行逆转录病毒介导的基因操作以灭活 靶分子(S)在正常以及肿瘤诱导的血管生成中的作用。通过 靶向正常和肿瘤诱导的相同信号成分 血管生成，我们会得到更好的画面，更好地比较 这两件事。因此，拟议的研究将勾勒出 血管内皮生长因子-A中的受体介导的信号转导，也将为 血管生成的分子机制。这些实验加在一起是 可能确定新的治疗靶点，以对抗血管生成 在肿瘤和其他疾病过程中也是如此。