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.
