The overall goal of this project is to determine the important cellular and molecular events during tissue repair and the local response to tumors and how they may be beneficially influenced by intervention. The cellular events that occur in the course of skin and corneal wound healing in animals will be analyzed systematically, with emphasis on matrix attachment components such as fibronectin and laminin and their receptors and determine how they may be altered by growth factors, particularly platelet derived growth factor (PDGF). The kinetics, distribution, and identity of cells that synthesize various fibronectin and PDGF and certain other matrix and growth factor molecules will be determined in pig skin and rabbit corneal wounds, using in situ hybridization with cDNA probes, immunoperoxidase, biochemical analysis and immunogold electron microscopy. The response of these wounds to recombinant PDGF, IGF- 1, EGF or TGF-beta alone or in combination will be tested. The anatomical relationship between the laminin, fibronectin and the cellular distribution of their receptors will be determined by immunogold electron microscopy. Antagonists to laminin and fibronectin receptors in the form of F(ab')2 antibodies or synthetic peptides will be used to determine the importance of cell attachment to this substrates in vivo. The biologic importance of binding of growth factors to matrix components, such as PDGF to collagen, will be examined. In vitro tests of epithelial migration and attachment will be developed using corneal organ culture and dissociated epithelial cells to determine the mechanisms by which fibronectin promotes epithelial healing in alkali burns. The connective tissue response around human tumors will be studied with the same cDNA and antibody probes to compare with the events that occur in normal healing. The proposed studies should provide in vivo relevance to phenomena hitherto observed in vitro. Advances in the understanding of repair processes and their control should lead to more rational intervention in wounds, chronic inflammatory processes and neoplasia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA020822-13
Application #
3481869
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1976-06-30
Project End
1992-12-31
Budget Start
1990-01-01
Budget End
1990-12-31
Support Year
13
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Nickeleit, V; Kaufman, A H; Zagachin, L et al. (1996) Healing corneas express embryonic fibronectin isoforms in the epithelium, subepithelial stroma, and endothelium. Am J Pathol 149:549-58
Nickeleit, V; Zagachin, L; Nishikawa, K et al. (1995) Embryonic fibronectin isoforms are synthesized in crescents in experimental autoimmune glomerulonephritis. Am J Pathol 147:965-78
Phan, T M; Foster, C S; Shaw, C D et al. (1991) Topical fibronectin in an alkali burn model of corneal ulceration in rabbits. Arch Ophthalmol 109:414-9
Frangieh, G T; Hayashi, K; Teekhasaenee, C et al. (1989) Fibronectin and corneal epithelial wound healing in the vitamin A-deficient rat. Arch Ophthalmol 107:567-71
Lynch, S E; Colvin, R B; Antoniades, H N (1989) Growth factors in wound healing. Single and synergistic effects on partial thickness porcine skin wounds. J Clin Invest 84:640-6