Angiogenesis during development, during healing and during tumor vascularization are processes which have major impact upon both an organism's ability to develop and survive. The control/modulation of angiogenesis is thought to involve integrated dynamic interactions among endothelial cells, extracellular matrix, soluble factors and other adjacent cell types. Advances in our understanding of these interactions in angiogenesis in the last several years have occurred in the areas of cell-cell, cell- matrix and cell-growth factor interactions. Cell-cell interactions between and among endothelial cells and endothelial cell-matrix interactions have been implicated in the various stages of the angiogenic process, including tube formation, maintenance and involution. Extracellular matrix-driven, integrin-mediated modulation of endothelial behavior has been shown to be critical in the angiogenic process. In particular, integrin modulation of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) phosphorylation has been shown to be an important regulator of angiogenesis both in vivo and in vitro. In particular, extracellular matrix-driven, integrin-mediated PECAM-1 tyrosine phosphorylation/dephosphorylation has been implicated in modulating endothelial cell migration, vasculogenesis and angiogenesis. Thus, the application proposes to elucidate the tyrosine and serine phosphorylation states of PECAM-1 and their effects on the conformation of the PECAM-1 ITAM domain, binding sites, and affinities for selected signalling and adapter molecules (c-src, SHPTP-2 and beta-catenin) and putative PECAM-1 - PECAM-1 interactions.
Each aim i s likely to provide novel information concerning PECAM-1. A particularly important aspect of this work is the use of 3D matrices to study endothelial biology. The investigator has been a leading figure in the use of the matrices. The environment is excellent for carrying out this work.
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