VEGF Induced Signal Transduction

VEGF 诱导的信号转导

• 批准号: 6986310
• 负责人: BRUCE I TERMAN
• 金额: $ 31.56万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-16 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986310
• 关键词: angiogenesis; angiogenesis inhibitors; biological signal transduction; growth factor receptors; molecular site; phosphorylation; protein protein interaction; protein structure function; protein tyrosine kinase; tissue /cell culture; transfection; vascular endothelial growth factors; vascular endothelium

DESCRIPTION: The growth of new blood capillaries from existing vessels (angiogenesis) is essential for development, tissue regeneration and remodeling. Angiogenesis also contributes to pathologic conditions including diabetic retinopathy and tumor growth, and anti-angiogenesis strategies are under clinical evaluation. Angiogenesis is a multi-step process involving endothelial cell proliferation, migration, and tube formation. Vascular Endothelial Growth Factor (VEGF) is a critical pro-angiogenic factor that stimulates multiple endothelial cell activities through binding to its receptor KDR. The long term goal of our research is clarify the signaling pathways that mediate these responses and to understand how the pathways are coordinated. VEGF-induced cell proliferation in mediated by the ERK1/2 MAPKinase. The signaling pathway leading to ERK1/2 activation involves the sequential activation of PLCg and PKC; this is unique when compared to many other growth factors which utilize Grb2 and Ras . VEGF-induced ERK1/2 activation is also dependent upon the generation of reactive oxygen species (ROS). The molecular interactions by which VEGF-induced ROS generation is coordinated with the PLCg-PKC pathway are not known; although our recent experimental results implicate the involvement of the SHP-1 protein tyrosine phosphatase. Experimental results that led to this conclusion include the finding that inhibition of SHP-1 by a dominant negative strategy mimics the effect of VEGF on ERK1/2 activation. We propose to validate this conclusion, and to further clarify VEGF-induced signaling mechanisms involved in cell proliferation by proposing three Specific Aims. AIM 1 is directed at clarifying SHP-1's role in neovascularization using an in vivo model; more specifically, vascular development in the mouse retina. AIM 2 is directed at further clarifying the molecular interactions involved in SHP-1 function by identifying SHP-1 substrates. AIM 3 is directed at clarifying the molecular interactions by which VEGF treatment modulates SHP-1 catalytic activity. Upon completion of these studies we will have clarified the earliest signaling events involved in VEGF-induced cell proliferation. The results obtained will be important in understanding how new blood vessels are formed, and will perhaps suggest new strategies for blocking pathological angiogenesis.

描述：从现有血管中生长出新的毛细血管(血管生成)对于发育、组织再生和重塑是必不可少的。血管生成也有助于包括糖尿病视网膜病变和肿瘤生长在内的病理情况，抗血管生成策略正在临床评估中。血管生成是一个多步骤的过程，涉及内皮细胞的增殖、迁移和管子的形成。血管内皮生长因子(VEGF)是一种重要的促血管生成因子，通过与其受体KDR结合，刺激多种血管内皮细胞的活动。我们研究的长期目标是阐明介导这些反应的信号通路，并了解这些通路是如何协调的。ERK1/2 MAPKinase介导的血管内皮生长因子诱导的细胞增殖导致ERK1/2激活的信号通路涉及PLCg和PKC的顺序激活；这与许多其他利用Grb2和RAS的生长因子相比是独一无二的。血管内皮生长因子诱导的ERK1/2的激活也依赖于活性氧的产生。虽然我们最近的实验结果暗示SHP-1蛋白酪氨酸磷酸酶参与了SHP-1蛋白酪氨酸磷酸酶的参与，但尚不清楚VEGF诱导的ROS产生与PLCg-PKC途径协调的分子相互作用。导致这一结论的实验结果包括发现，通过显性否定策略抑制SHP-1类似于VEGF对ERK1/2激活的影响。我们建议通过提出三个特定的目标来验证这一结论，并进一步阐明血管内皮生长因子诱导的信号转导机制参与细胞增殖。目的1旨在利用体内模型阐明SHP-1‘S在新生血管中的作用；更具体地说，是关于小鼠视网膜的血管发育。目的2旨在通过鉴定SHP-1底物进一步阐明参与SHP-1功能的分子相互作用。目的3旨在阐明血管内皮生长因子处理调节SHP-1催化活性的分子相互作用。在这些研究完成后，我们将阐明与血管内皮生长因子诱导的细胞增殖有关的最早信号事件。所获得的结果将对了解新血管是如何形成的很重要，并可能为阻断病理性血管生成提供新的策略。