Vascular endothelial cell growth factor (VEGF) is a highly specific chemotactic and mitogenic factor for cultured endothelial cells (EC) and an angiogenesis factor in vivo. It binds to 180 and 200 kDa high affinity tyrosine kinase receptors, Flt-1 and KDR/Flk-1, respectively, found primarily on EC. Recently, a relatively lower affinity 120-130 kDa receptor has been identified on EC and tumor cell lines that binds VEGF165, but not VEGF121, and accordingly has been designated as the VEGF165 receptor (VEGF165R). VEGF165 R does not appear to be related to KDR/Flk-1 and Flt-1 since it is not immunoprecipitated by antibodies to these receptors. The binding of VEGF165 to VEGF165R is mediated by the protein domain encoded by exon 7, which is lackin2 x 10(-9) M g in VEGF121. An exon 7- encoded fusion protein inhibits VEGF165 binding to EC and tumor cells.
The Specific Aims of this proposal are: 1. Characterization of a cell surface receptor (VEGF165R) that binds VEGF165 but not VEGF121 including: a) identification of a cell types that express this receptor; b) binding of VEGF family ligands; c) modulation of proliferation, migration and morphology by VEGF165R; and d) VEGF165R receptor phosphorylation and signaling; 2. Purification and cloning of the VEGF165 receptor and antibody production including: a)purification of VEGF165R; b)expression cloning of VEGF165R; c) production of anti-VEGF165R in cells; 3. Characterization of exon 7- encoded protein, an inhibitor of VEGF165 binding to EC and tumor cells including: a) Preparation of exon 7 protein by fusion protein methods; b) measuring inhibitory effects of exon 7-encoded protein on VEGF165 binding to, and mitogenic and chemotactic activity for, EC and tumor cells; c) preparatio of anti exon 7 protein neutralizing antibodies to inhibit VEGF165 binding to VEGF165R; d) determination of the core inhibitory amino acid sequence within the exon 7 protein domain; and e) production of a chimeric exon 7 protein-diphtheria toxin fusion protein for tumor cell and tumor EC targeting.
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