Distinct Pathways of VPF/VEGF Receptors

血管生成，通常被称为从现有的血管床形成新的血管，是紧密的 受正负代谢途径的平衡调节。因为它在肿瘤形成中起着中心作用， 非肿瘤性疾病，包括先兆子痫、肺动脉高压、眼部微血管增生症 疾病、新血管内膜形成和再狭窄，以及在正常成人生理中，血管生成 最近引起了科学界的极大兴趣。具有血管生成活性的生长因子包括 血管通透性因子/血管内皮生长因子(VEGF-A)、胎盘生长因子(PIGF)、 成纤维细胞生长因子和血小板衍生生长因子B链。可以说，血管内皮生长因子-A是最重要的 血管生成细胞因子在肿瘤中的表达及阻断血管内皮生长因子-A信号通路有望发挥作用 控制肿瘤血管生成，从而限制甚至逆转肿瘤生长。然而，有一些 还有我们需要促进平衡血管生成的疾病，包括心血管疾病。 限制合理的抗或促血管生成治疗发展的一个主要因素是我们的不完全 了解血管内皮生长因子-A信号转导内皮细胞的基本步骤和分子机制 通过其两个高亲和力酪氨酸激酶受体VEGFR-1和VEGFR-2的增殖和迁移。 目前的信息表明，这些受体在血管生成和血管生成中具有不同的作用。 并调节不同的信号通路。此外，新出现的证据表明，通过VEGFR发出的信号- 1实际上抑制了部分但不是所有通过VEGFR-2介导的功能。中国的长期目标是 目前的应用是阐明VEGFR-1和VEGFR-2介导的不同的信号通路。 内皮细胞。目标1将定义PLC Y1和(VEGFR中的33个异构体)的激活机制和作用 2-介导的信号通路，而Aim 2将区分Rho A，B和C在VEGFR-2中的作用- 中介信号。最后，目标3将研究VEGFR-1对血管内皮细胞的调节作用 PI-3K和CDC42在血管成熟中的新作用。我们的实验将包括利用EC 组织培养系统、检测血管发育的斑马鱼模型和肿瘤诱导的血管生成 所有目标的典范。这些研究将绘制负责血管生成的关键信号通路和 在这个过程中，找出调节这些途径的关键分子。因此，这些建议的结果 研究将有助于确定潜在的血管生成抑制物或促进剂，这些抑制剂或促进剂可以靶向并用于 改进未来针对不同疾病的治疗方法。

Angiogenesis, typically known as the formation of new blood vessels from an existing vascular bed, is tightly regulated by a balance of positive and negative metabolic pathways. Because of its central role in neoplasia, non-neoplastic disorders including preeclampsia, pulmonary hypertension, ocular microvascular proliferative disorders, neointima formation and restenosis, and also in normal adult physiology, angiogenesis has recently attracted a great deal of scientific interest. Growth factors possessing angiogenic activity include vascular permeability factor/vascular endothelial growth factor (VEGF-A), placenta growth factor (PIGF), fibroblast growth factor, and platelet derived growth factor B chain. VEGF-A is arguably the most important angiogenic cytokine expressed by tumors and it is expected that blocking VEGF-A signaling will be effective in controlling tumor angiogenesis and therefore, limiting or even reversing tumor growth. However, there are also diseases where we need to promote balanced angiogenesis and these include cardiovascular diseases. A major factor limiting the development of rational anti- or pro-angiogenesis therapy is our incomplete understanding of the basic steps and molecular mechanisms by which VEGF-A signals endothelial cell proliferation and migration through its two high affinity tyrosine kinase receptors VEGFR-1 and VEGFR-2. Current information indicates that these receptors have different roles in vasculogenesis and angiogenesis and mediate different signaling pathways. Also, emerging evidence suggests that signaling through VEGFR- 1 actually inhibits some but not all of the functions mediated through VEGFR-2. The long-term goal of the current application is to elucidate the distinct signaling pathways mediated by VEGFR-1 and VEGFR-2 in endothelial cells. Aim 1 will define an activation mechanism and role for PLC yl and (33isoforms in VEGFR- 2-mediated signaling pathways whereas Aim 2 will distinguish the role of Rho A, B, and C in VEGFR-2- mediated signaling. Finally, Aim 3 will investigate the regulatory role of VEGFR-1 on vascular endothelium and a novel role for PI-3K and CDC42 in vessel maturation. Our experiments will include utilizing an EC tissue culture system, a zebrafish model to detect vascular development, and tumor-induced angiogenic models for all Aims. These studies will map the critical signaling pathways responsible for angiogenesis and in the process, identify key molecules that mediate these pathways. Hence, the results of these proposed studies will help identify potential angiogenic inhibitors or promoters that can be targeted and used to improve future therapies against different diseases.