Our primary goal is to inhibit the angiogenic process through the specific antagonism of a growth factor-receptor interaction. Although an absolute requirement for the proper development of a growing fetus, angiogenesis in adults has been associated with numerous disease states, including the growth of solid tumors, diabetic retinopathy, rheumatoid arthritis and psoriasis. Recently, a direct link between angiogenesis and tumor metastasis has been established, further emphasizing the need for novel pharmaceuticals that specifically regulate angiogenesis. Among the most prominent mediators of angiogenesis are members of the fibroblast growth factor (FGF) family. Monomeric FGF interacts with FGF receptors (FGFR) and heparan sulfate proteoglycans in a highly specific manner on cell surfaces that leads to FGFR dimerization, thus initiating the signal transduction cascade resulting in cell proliferation. We will inhibit the interactions of FGF with its cognate receptor by employing a protein structure an mechanism based approach in which an engineered FGF will prevent FGFR dimerization. This will be accomplished through the modification of receptor binding sites on FGF by site-directed mutagenesis. A second component of this proposal will be the development of a more potent FGF. This will be accomplished by enhancing the binding affinity of FGF to FGFR by protein structure- based site-directed mutagenesis. FGFs are also potent mediators of the wound healing process and formulations of FGF are currently in clinical trials to accelerate the healing process. A more potent FGF would serve to decrease the amount of protein required to achieve the same therapeutic result.National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
