VEGF Induced Signal Transduction

描述：现有血管新生毛细血管的生长（血管生成）对发育、组织再生和重塑至关重要。血管生成还有助于糖尿病视网膜病变和肿瘤生长等病理条件，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，包括内皮细胞增殖、迁移和管的形成。血管内皮生长因子（Vascular Endothelial Growth Factor， VEGF）是一种重要的促血管生成因子，通过与其受体KDR结合刺激多种内皮细胞的活性。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vegf诱导细胞增殖。导致ERK1/2激活的信号通路涉及PLCg和PKC的顺序激活；与许多其他利用Grb2和Ras的生长因子相比，这是独一无二的。vegf诱导的ERK1/2激活也依赖于活性氧（ROS）的产生。vegf诱导的ROS生成与PLCg-PKC通路协调的分子相互作用尚不清楚；尽管我们最近的实验结果暗示了SHP-1蛋白酪氨酸磷酸酶的参与。得出这一结论的实验结果包括发现通过显性阴性策略抑制SHP-1模拟了VEGF对ERK1/2激活的影响。我们建议验证这一结论，并通过提出三个具体目标来进一步阐明vegf诱导的细胞增殖信号机制。AIM 1旨在通过体内模型阐明SHP-1在新生血管形成中的作用；更具体地说，是小鼠视网膜的血管发育。AIM 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。AIM 3旨在阐明VEGF治疗调节SHP-1催化活性的分子相互作用。在完成这些研究后，我们将澄清vegf诱导的细胞增殖中涉及的最早信号事件。所获得的结果对于理解新血管是如何形成的很重要，并且可能会提出阻止病理性血管生成的新策略。

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.