Our investigative efforts will be concentrated in 3 areas: (1) determining the role of the insulin-like growth factors in the development of diabetic retinopathy, (2) investigating the role of specific binding proteins in controlling IGF action, and (3) defining the role of these factors in normal growth and development, particularly as they relate to pubertal growth and sexual maturation. In the first category above, we will study the actions of the insulin-like growth factors (IGF I and IGF II) and growth hormone (GH) on two critical steps involved in neovascularization of the retina: First, the role of these factors in controlling the dissolution of capillary basement membranes and the matrix which surrounds retinal endothelial cells and second, the action of these agents in controlling subsequent migration of retinal endothelial cells (chemotaxis). Enzyme assays for the measurement of collagenase III and IV and techniques for the study of chemotaxis are functional in the Principle Investigator's laboratory. In preliminary work we have demonstrated that both IGF I and GH effect each of the major steps listed above. The ability of pericytes, retinal pigment epithelial cells and other substances in vitreous to modulate IGF and GH action will be examined comprehensively in in vitro and in vivo studies. Human retinal endothelial cells, pigment epithelial cells, and pericytes are maintained in culture for this purpose and we obtain bovine cells as needed. We will likewise continue characterization of the serum proteins that bind IGF I and II with particular emphasis on the role of these proteins in major pathological states. These binding proteins are important in that they unquestionably alter both the distribution and action of the growth factors. We will investigate the role of IGF I and II in modulating normal growth and development with particular emphasis on defining the role of IGF I in controlling normal pubertal growth and in controlling carrier protein expression. We have the capacity to assay specifically IGF I and IGF II as well as the capacity for IGF to study multiple processes involved in neovascularization. We have made major advances in the biochemical purification of the carrier proteins for IGF. To the Senior Investigator's knowledge there is no single laboratory in the United States with comparable capacity and a record that demonstrates this capacity.
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| Grant, M B; Mames, R N; Fitzgerald, C et al. (1993) Insulin-like growth factor I acts as an angiogenic agent in rabbit cornea and retina: comparative studies with basic fibroblast growth factor. Diabetologia 36:282-91 |
| Grant, M B; Khaw, P T; Schultz, G S et al. (1992) Effects of epidermal growth factor, fibroblast growth factor, and transforming growth factor-beta on corneal cell chemotaxis. Invest Ophthalmol Vis Sci 33:3292-301 |
| Grant, M B; Guay, C; Marsh, R (1990) Insulin-like growth factor I stimulates proliferation, migration, and plasminogen activator release by human retinal pigment epithelial cells. Curr Eye Res 9:323-35 |
| Baumann, G; Shaw, M A; Merimee, T J (1989) Low levels of high-affinity growth hormone-binding protein in African pygmies. N Engl J Med 320:1705-9 |
