Basic fibroblast growth factor (bFGF), heparin-binding EGF-like growth factor (HB-EGF) and vascular endothelial growth factor (VEGF) are heparin- binding growth factors that regulate endothelial cell (bFGF,VEGF) and smooth muscle cell (bFGF, HB-EGF) proliferation. They have been implicated in mediating tumor angiogenesis and smooth muscle cell hyperplasia in vivo. Recent studies have demonstrated that primary cultures of human T lymphocytes and tumor infiltrating lymphocytes synthesize bFGF and HB-EGF mRNA and export bFGF and HB-EGF-like growth factor activities. Synthesis of vascular cell growth factors by T cells may be significant since these cells infiltrate wounds, tumors and atherosclerotic plaques. The bFGF-like activity synthesized by T cells is atypical in that a substantial amount is exported suggesting that T cells produce an altered form of bFGF or have a novel mechanism of exporting bFGF. The affinity of bFGF, HB-EGF and VEGF for heparin is biologically significant since these growth factors need to interact with cell surface HSPG in order to bind to high affinity receptors and to have optimal mitogenic activity. The overall goals of the proposal are to investigate the structural and biological properties of these three heparin-binding vascular cell growth factors with an emphasis on, i) characterizing, purifying and cloning T cell growth factors and determining whether T cell bFGF is a novel member of the FGF family or has a novel mechanism of export, ii) analyzing the structural and biological mechanisms that mediate growth factor dependence on interactions with cell surface HSPG, and iii) analyzing VEGF, HB-EGF and bFGF expression and the significance thereof in tumors.
The SPECIFIC AIMS of this proposal are: (1). To characterize T Lymphocyte-derived bFGF- and HB-EGF-like cell growth factors in vitro and in vivo including a) purification, sequencing and cloning, b) analysis of possible mechanisms of T cell bFGF export, and c) analysis of their expression in T cells in tumors and vascular disease; (2). To analyze and compare the heparin-binding properties of bFGF, HB-EGF and VEGF including: a) analysis of the heparin-dependence of the mitogenic activity of these growth factors, b) identification of VEGF heparin-binding domains and comparing them to other heparin-binding domains, c) characterization and purification of a novel inducer of syndecan synthesis, a potential regulator of heparin-binding growth factor activity and d) expressing the heparinase 1 gene in mammalian cells as a novel method for ascertaining the role of HSPG in mediating growth factor activity; (3). To investigate VEGF and HB-EGF expression in prostate cancer.
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