Xerophthalmia is a leading cause of world blindness. Clinical and experimental observations have led to the central hypothesis that he vitamin A-deficient (A-) cornea is abnormally susceptible to trauma and infection, leading to an abnormally accelerated inflammatory response, increased collagenolytic activity, and resultant stromal ulceration (keratomalacia). The long-term objective is to establish to interrelationship between vitamin A status and the abnormal corneal response to injury and infection. This will improve understanding of the pathogenesis of xerophthalmia and the treatment of keratomalacia. A well-characterized nutritional model, the A- rat, will be utilized in clinical, biochemical, immunologic, and morphologic studies. The proposed Specific Aims are as follows: 1. Wound healing: to determine why A- corneal epithelium is wounded easily and heals slowly. (Ultrastructural morphometric analysis will quantitate abnormality of the corneal epithelia adhesion complexes, and in vivo and organ culture studies will further characterize the known deficiencies of fibronectin and plasminogen activator in the healing A- cornea.) 2. Infection: to examine the mechanism of increased bacterial adhesion to the A- ocular surface. (Concanavalin A binding to the surface glycoproteins of unwounded A- corneal epithelium will be ultrastructurally quantitated. Bacterial adhesion to corneal epithelium through mannose residues will be determined by SEM.) 3. Inflammation: to detect chemotactic factors (CF) for polymorphonuclear neutrophils in A- corneas that could account for the abnormal inflammatory response after minor wounding. (Boyden chamber methodology will assess CFs from wounded A- corneas, and specific assays will quantitate C5a, IL-1, and possibly unique CFs in A- corneas.) 4. Ulceration: to characterize the source of collagenase in injured A- corneas and to examine protease gene expression and activity in A- keratocytes. (Enzymatic and immunoassays will complement studies using a cDNA probe for protease mRNA to characterize the interactions of A- corneal epithelium, keratocytes, and polymorphonuclear neutorphils in vitro.)

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY005799-07
Application #
3261372
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1985-07-01
Project End
1994-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
7
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Schepens Eye Research Institute
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02114
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
Udell, I J; Kenyon, K R; Hanninen, L A et al. (1989) Time course of human conjunctival mast cell degranulation in response to compound 48/80. Acta Ophthalmol Suppl 192:154-61