Distinct Pathways of VPF/VEGF Receptors

VPF/VEGF 受体的独特途径

• 批准号: 7388094
• 负责人: DEBABRATA MUKHOPADHYAY
• 金额: $ 35.93万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388094
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adult; Affinity; Angiogenesis Inhibitors; Angiogenic Factor; Biochemical; Biological; Biological Assay; Biological Models; Blood Vessels; CDC42 gene; Cardiovascular Diseases; Cell Proliferation; Chinese Hamster Ovary Cell; Chronic; Defect; Development; Developmental Biology; Diabetic Retinopathy; Disease; Endothelial Cells; Epidermal Growth Factor Receptor; Equilibrium; Event; Experimental Designs; Family member; Fibroblast Growth Factor; Future; Goals; Growth Factor; Implant; In Vitro; Individual; Inflammation; Knockout Mice; Knowledge; Link; Malignant Neoplasms; Maps; Measurement; Mediating; Metabolic Pathway; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mus; N-terminal; Nature; Neoplasms; Ocular Hypertension; Pathogenesis; Pathologic Neovascularization; Pathway interactions; Pattern; Phospholipase C; Physiology; Placental Growth Factor; Pre-Eclampsia; Process; Protein Family; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-sis; Pulmonary Hypertension; Receptor Protein-Tyrosine Kinases; Research Personnel; Role; Signal Pathway; Signal Transduction; Signaling Molecule; System; Tumor Angiogenesis; Tyrosine; VEGFR inhibition; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascular Endothelium; Vascular Permeabilities; Zebrafish; angiogenesis; cdc42 GTP-Binding Protein; cytokine; embryonic stem cell; improved; in vivo; in vivo Model; interest; migration; mutant; neointima formation; neoplastic; novel; promoter; receptor; reconstitution; research study; restenosis; rho; rho GTP-Binding Proteins; therapeutic angiogenesis; tissue culture; tool; tumor; tumor growth; vascular bed; vasculogenesis

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.

血管生成，通常称为现有血管床形成新血管的形成，紧密 由正和负代谢途径的平衡调节。由于其在肿瘤中的核心作用， 非肿瘤疾病，包括先兆子痫，肺动脉高压，眼微血管增殖 疾病，新内膜形成和再狭窄，以及在正常的成人生理学中，血管生成具有 最近引起了很多科学兴趣。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（PIGF）， 成纤维细胞生长因子和血小板得出的生长因子B链。 VEGF-A可以说是最重要的 由肿瘤表达的血管生成细胞因子，预计阻断VEGF-A信号将有效 在控制肿瘤血管生成，因此，限制甚至逆转肿瘤生长。但是，有 还需要促进平衡血管生成的疾病，其中包括心血管疾病。 限制理性抗血管生成疗法发展的主要因素是我们的不完整 了解VEGF-A信号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。 当前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 并介导不同的信号通路。此外，新兴的证据表明，通过VEGFR的信号传导 1实际上抑制了通过VEGFR-2介导的一些但不是所有功能。长期目标 当前的应用是为了阐明由VEGFR-1和VEGFR-2介导的不同信号通路 内皮细胞。 AIM 1将定义PLC YL的激活机制和作用（VEGFR-中的33种异型 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。 介导的信号传导。最后，AIM 3将研究VEGFR-1对血管内皮的调节作用 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，一种检测血管发育的斑马鱼模型，肿瘤诱导的血管生成 所有目标的模型。这些研究将绘制负责血管生成的关键信号通路和 在此过程中，确定介导这些途径的关键分子。因此，这些提出的结果 研究将有助于确定可以针对和习惯的潜在血管生成抑制剂或启动子 改善对不同疾病的未来疗法。