The fundamental purpose of these studies is to identify the growth factors that stimulate proliferation in blood vessel wall cell types and to determine the mechanisms by which they exert their effects. Cultured porcine aortic smooth muscle and endothelial cells will be used to determine the target cell actions of several mitogens. Smooth muscle cells appear to autoregulate their rates or replication in culture and this autoregulation is partially controlled by the cellular secretion of a somatomedin (Sm) like peptide. Studies will be initiated to determine if blocking the secretion of the Sm-like peptide with a specific monoclonal anti-Sm-C antibody alters the smooth muscle cell response to other growth factors. The Sm-like peptide will be further purified and its physicochemical properties determined. Since the Sm-like peptide is secreted and then rebinds as cell surface receptor, the factors that regulate Sm-C cell surface receptor concentration will be analyzed. The effect of a recently identified peptide that is secreted by fibroblasts on 125I-Sm-C binding to the smooth muscle cell surface will be determined. This factor will be purified and studies will be initiated to determine if it enhances the biologic response to Sm-C. Heparin is a potent inhibitor of smooth muscle cell growth. Since heparin alters the affinity of Sm-C for it's plasma binding protein, we will determine if it alters Sm-C binding to smooth muscle cells or the cellular DNA synthesis response to Sm-C. The effects of two recently discovered platelet derived mitogens on endothelial replication will be analyzed. Both factors will be purified to homogeneity and their chemical structures determined. The effects of pure mitogens on the endothelial cell response to peptide growth factors will be determined. The factors that mediate the release of these mitogens from platelets will be studied. Since two specific nucleotides are mitogens for endothelium, the capacity of these two nucleotides to be transported across endothelium will be compared to smooth muscle cells (a non-responsive cell type). Platelets appear to release a peptide inhibitor that specifically inhibits the effects of the endothelial mitogens. This inhibitor will be purified and its effect on the induction of DNA synthesis by purified growth factors determined. The results of these studies should provide basic information that is necessary to construct valid hypotheses regarding the role of these growth factors in the development of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036313-02
Application #
3351238
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1986-07-01
Project End
1991-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Young, S C; Clemmons, D R (1994) Changes in insulin-like growth factor (IGF)-binding proteins after IGF-I injections in noninsulin-dependent diabetics. J Clin Endocrinol Metab 78:609-14
Clemmons, D R; Jones, J I; Busby, W H et al. (1993) Role of insulin-like growth factor binding proteins in modifying IGF actions. Ann N Y Acad Sci 692:10-21
McCusker, R H; Cohick, W S; Busby, W H et al. (1991) Evaluation of the developmental and nutritional changes in porcine insulin-like growth factor-binding protein-1 and -2 serum levels by immunoassay. Endocrinology 129:2631-8
Clemmons, D R; Underwood, L E (1991) Nutritional regulation of IGF-I and IGF binding proteins. Annu Rev Nutr 11:393-412
Clemmons, D R; Gardner, L I (1990) A factor contained in plasma is required for IGF binding protein-1 to potentiate the effect of IGF-I on smooth muscle cell DNA synthesis. J Cell Physiol 145:129-35
Clemmons, D R; Cascieri, M A; Camacho-Hubner, C et al. (1990) Discrete alterations of the insulin-like growth factor I molecule which alter its affinity for insulin-like growth factor-binding proteins result in changes in bioactivity. J Biol Chem 265:12210-6
Tollefsen, S E; Lajara, R; McCusker, R H et al. (1989) Insulin-like growth factors (IGF) in muscle development. Expression of IGF-I, the IGF-I receptor, and an IGF binding protein during myoblast differentiation. J Biol Chem 264:13810-7
McCusker, R H; Campion, D R; Jones, W K et al. (1989) The insulin-like growth factor-binding proteins of porcine serum: endocrine and nutritional regulation. Endocrinology 125:501-9
Busby, W H; Hossenlopp, P; Binoux, M et al. (1989) Purified preparations of the amniotic fluid-derived insulin-like growth factor-binding protein contain multimeric forms that are biologically active. Endocrinology 125:773-7
McCusker, R H; Camacho-Hubner, C; Clemmons, D R (1989) Identification of the types of insulin-like growth factor-binding proteins that are secreted by muscle cells in vitro. J Biol Chem 264:7795-800

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