Vascular endothelial growth factor (VEGF) signaling controls blood vessel development and plays a central role in the vascularization of malignant tumors. The most important receptors for VEGF are part of the receptor tyrosine kinase (RTK) family. Receptor dimerization is an important step in the activation of RTK receptors. Concentration or clustering of receptors in islands representing a small fraction of the total membrane surface is another feature of RTK signaling, believed to increase its efficiency. The role of these phenomena in signaling and the origin and mechanism of receptor clustering are not well understood and are subject to intense experimental and theoretical efforts. This project on VEGF complements ongoing work focused on other RTK receptor families such as EGF. We propose to investigate the role of spatial structure in the kinetics of VEGF signaling and infer the spatial distribution of VEGF receptors in the cell membrane and its dependence on the presence of ligand, in a specific cell system. Experimentally we plan to use advanced imaging methods which allow the visualization of individual receptors and infer their spatial distribution and mobility, as well as flow cytometry to investigate signaling in individual cells. Based on data collected on the same cellular system, we will build a spatial Monte-Carlo model of the molecular processes involved in signaling, including two-dimensional movement in the cell membrane. We will use this model to investigate the interplay between spatial features of the cell membrane, receptor clustering, and signal transduction. Finally, we seek to encapsulate the emerging understanding of spatial aspects of VEGF binding in lower dimensional representations, with the goal of defining a realistic, whole-cell model of the first step in VEGF signaling, which can be incorporated in models on the scale of tissues.
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