Distinct Pathways of VPF/VEGF Receptors

描述（由申请人提供）：血管生成，通常称为从现有血管床形成新血管，受到正代谢途径和负代谢途径平衡的严格调节。由于其在肿瘤形成、非肿瘤性疾病（包括先兆子痫、肺动脉高压、眼微血管增生性疾病、新生内膜形成和再狭窄）以及正常成人生理学中的中心作用，血管生成最近吸引了大量的科学兴趣。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（PlGF）、成纤维细胞生长因子和血小板衍生生长因子B链。VEGF-A可以说是由肿瘤表达的最重要的血管生成细胞因子，并且预期阻断VEGF-A信号传导将有效地控制肿瘤血管生成，从而限制甚至逆转肿瘤生长。然而，也有一些疾病，我们需要促进平衡的血管生成，这些疾病包括心血管疾病。限制合理的抗血管生成或促血管生成治疗发展的一个主要因素是我们对VEGF-A通过其两种高亲和力酪氨酸激酶受体VEGFR-1和VEGFR-2信号内皮细胞增殖和迁移的基本步骤和分子机制的不完全理解。目前的信息表明，这些受体在血管发生和血管生成中具有不同的作用，并介导不同的信号转导途径。此外，新出现的证据表明，通过VEGFR- 1的信号传导实际上抑制了通过VEGFR-2介导的部分但不是全部功能。本申请的长期目标是阐明内皮细胞中由VEGFR-1和VEGFR-2介导的不同信号传导途径。目的1将定义PLC γ 1和β 3同种型在VEGFR- 2介导的信号传导途径中的活化机制和作用，而目的2将区分Rho A、B和C在VEGFR-2介导的信号传导中的作用。最后，目的3将研究VEGFR-1对血管内皮的调节作用以及PI-3 K和CDC 42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用于所有目的的肿瘤诱导的血管生成模型。这些研究将绘制负责血管生成的关键信号通路，并在此过程中确定介导这些通路的关键分子。因此，这些拟议研究的结果将有助于确定潜在的血管生成抑制剂或促进剂，这些抑制剂或促进剂可以被靶向并用于改善未来针对不同疾病的治疗。

DESCRIPTION (provided by applicant): 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 (33 isoforms 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.