The fibroblast growth factors (FGF's) are a growing family of structurally related polypeptide mitogens. FGF's are particularly mitogenic for vascular endothelial cells and smooth muscle cells, and they are among the most potent angiogenic substances known. Over the past year, our laboratory has cloned several members of what may be family of FGF receptors. The long term goal of this research is to define fundamental properties of FGF receptor biology, i.e. which FGF ligands do they bind, what intracellular signaling pathways do they use, and what is their pattern of expression during normal vascular growth and in vascular diseases. To study ligand binding specificity individual FGF receptors will be expressed in cells that normally do not express the receptor, and then tested for interaction with various FGF ligands by equilibrium binding assays and functional assays. After ligand binding, activated growth factor receptors interact with signaling pathways that determine the response of the cell. Recent studies, from our laboratory and others, have shown that ligand-activated grow factor receptors, such as the PDGF and EGF receptors, form complexes with potentially important signaling molecules that are subsequently phosphorylated and possibly activated by growth factor receptor tyrosine kinases. Since proteins important in FGF signaling may, likewise, by physically associated with ligand-activated FGF receptors, they will be identified by coimmunoprecipitation from lysates of FGF-treat cells using FGF receptor antibodies. The availability of FGF receptors may limit vascular growth, and factors that influence vascular growth may do so via regulation of FGF receptor expression. Furthermore, abnormal expression of FGF receptors may contribute to the development of vascular diseases. Regulation of FGF receptor expression will be studied in a simple model of endothelial cell differentiation that resembles angiogenesis using immunoblot and northern blot analysis. Moreover, the pattern of FGF and FGF receptor expression in normal versus pathologic tissues will be compared at the cellular level using in situ hybridization and immunocytochemistry. The conceptual framework provided by these studies may eventually lead to the development of new therapeutic approaches for the management or prevention of vascular disease.
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