Abstract

The long term goal of this proposal is to determine the role of polypeptide growth factors in the regulation of endothelial cell migration, proliferation and differentiation. Multiple forms of endothelial cell growth factor (ECGF) have been identified and their primary structures elucidated. Similarly multiple functions are indicated for this family of polypeptides.
The specific aims of the proposal are (1) to characterize the functional domains of ECGF and to correlate these domains with structural domains of the polypeptides; (2) to determine the extent to which structural features that are common to both ECGF and basic fibroblast growth factor (FGF) reflect common functions; (3) to determine whether acidic FGF and alpha-ECGF result from post- translational processing of beta-ECGF and (4) to extend our data on the human ECGF cDNA sequence to include analysis of the structure of the gene encoding ECGF and to compare its structure to that of the gene for basic-FGF. These studies will provide a structural basis for establishing the mechanism of action of factors that modulate endothelial cell growth and differentiation such as heparin. In addition, it is anticipated that these studies will result in the identification of specific peptidic and immunological modulators of endothelial cell growth and migration. The availability of such modulators should have a significant impact on studies of atherosclerosis, wound healing and other hemostatic or pathophysiological processes involving the vascular wall. The studies will involve testing the ability of enzymatic or chemically derived fragments of ECGF to either mimic or inhibit the mitogenic and chemotactic activities of the intact polypeptide. Site specific and site directed antibodies of ECGF will be generated and characterized as modulators of ECGF action. Comparative functional studies with basis FGF will be completed and the genes for ECGF and basic-FGF will be studied to determine the evolutionary relationships and the pre-pro relationships of the isolated polypeptides.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL035762-02
Application #
3350006
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1987-08-01
Project End
1990-07-31
Budget Start
1987-08-01
Budget End
1988-07-31
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
American National Red Cross
Department
Type
DUNS #
003255213
City
Washington
State
DC
Country
United States
Zip Code
20037

  Publications

Dunstan, C R; Boyce, R; Boyce, B F et al. (1999) Systemic administration of acidic fibroblast growth factor (FGF-1) prevents bone loss and increases new bone formation in ovariectomized rats. J Bone Miner Res 14:953-9
Wong, P; Hampton, B; Szylobryt, E et al. (1995) Analysis of putative heparin-binding domains of fibroblast growth factor-1. Using site-directed mutagenesis and peptide analogues. J Biol Chem 270:25805-11
Isakov, N; Wange, R L; Burgess, W H et al. (1995) ZAP-70 binding specificity to T cell receptor tyrosine-based activation motifs: the tandem SH2 domains of ZAP-70 bind distinct tyrosine-based activation motifs with varying affinity. J Exp Med 181:375-80
Basilion, J P; Rouault, T A; Massinople, C M et al. (1994) The iron-responsive element-binding protein: localization of the RNA-binding site to the aconitase active-site cleft. Proc Natl Acad Sci U S A 91:574-8
Burgess, W H; Friesel, R; Winkles, J A (1994) Structure-function studies of FGF-1: dissociation and partial reconstitution of certain of its biological activities. Mol Reprod Dev 39:56-60;discussion 60-1
Zhan, X; Hu, X; Hampton, B et al. (1993) Murine cortactin is phosphorylated in response to fibroblast growth factor-1 on tyrosine residues late in the G1 phase of the BALB/c 3T3 cell cycle. J Biol Chem 268:24427-31
Egerton, M; Ashe, O R; Chen, D et al. (1992) VCP, the mammalian homolog of cdc48, is tyrosine phosphorylated in response to T cell antigen receptor activation. EMBO J 11:3533-40
Hampton, B S; Marshak, D R; Burgess, W H (1992) Structural and functional characterization of full-length heparin-binding growth associated molecule. Mol Biol Cell 3:85-93
Burgess, W H; Shaheen, A M; Hampton, B et al. (1991) Structure-function studies of heparin-binding (acidic fibroblast) growth factor-1 using site-directed mutagenesis. J Cell Biochem 45:131-8
Burgess, W H (1991) Structure-function studies of acidic fibroblast growth factor. Ann N Y Acad Sci 638:89-97

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