Virtually all endothelial cell growth factors can be purified by heparin affinity chromatography. These heparin-binding growth factors (HBGF's) fall into two classes. Class 1 HBGF's are anionic mitogens found in high levels in neural tissue, and class 2 HBGF's are cationic mitogens with a wide tissue distribution. Both classes of HBGF induce angiogenesis and are likely to play a role in the neovascularization that occurs in a variety of normal and pathological processes, including wound healing, ovulation, abnormal retinal neovascularization, arthritis, and particularly solid tumor growth. Thus, the importance of HBGF's and heparin as modulators of endothelial cell function and blood vessel growth has significant pathological and therapeutic implications. Investigations into their physiological relevance will depend critically on a thorough understanding of the structural basis for the interaction of HBGF's with their cell receptors and the heparin molecule.
The specific aim of this proposal is to examine the relationship between the structure and function of the class 1 HBGF from bovine brain (HBGF-1), which is typical of all class 1 HBGF's. This relationship will be evaluated by: determination of the complete structure of HBGF-1 by the complementary approaches of protein and cDNA sequencing; definition of assays that provide accurate readouts of the interaction between heparin, HBGF-1, and the cell receptor; chemical and enzymatic modification of HBGF-1; evaluation of synthetic peptides representing fragments of HBGF-1 as agonists or antagonists; and evaluation of the effects of antibodies of defined specificity. The goal of these structure/function studies is the development of chemical and/or immunological agonists and antagonists capable of modulating the functions of class 1 HBGF's in vivo.
|Damon, D H; Lobb, R R; D'Amore, P A et al. (1989) Heparin potentiates the action of acidic fibroblast growth factor by prolonging its biological half-life. J Cell Physiol 138:221-6|
|Harper, J W; Lobb, R R (1988) Reductive methylation of lysine residues in acidic fibroblast growth factor: effect on mitogenic activity and heparin affinity. Biochemistry 27:671-8|
|Lobb, R R (1988) Thrombin inactivates acidic fibroblast growth factor but not basic fibroblast growth factor. Biochemistry 27:2572-8|
|Lobb, R R (1988) Clinical applications of heparin-binding growth factors. Eur J Clin Invest 18:321-36|
|Rybak, S M; Lobb, R R; Fett, J W (1988) Comparison of the effects of class 1 and class 2 heparin-binding growth factors on protein synthesis and actin mRNA expression in BALB/c-3T3 cells. J Cell Physiol 136:312-8|
|Halperin, J A; Lobb, R R (1987) Effect of heparin-binding growth factors on monovalent cation transport in Balb/C 3T3 cells. Biochem Biophys Res Commun 144:115-22|
|Lobb, R R; Rybak, S M; St Clair, D K et al. (1986) Lysates of two established human tumor lines contain heparin-binding growth factors related to bovine acidic brain fibroblast growth factor. Biochem Biophys Res Commun 139:861-7|