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. ? ?
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