Investigator's description): There is a significant need to discover the basic molecular mechanisms responsible for corneal inflammation and ulceration in the alkali-injured eye. This project attacks the afferent limb of the inflammatory reaction by attempting to inhibit the chemoattractants which lure PMNs into the damaged corneal tissue. Previous studies discovered that the alkali-injured eye elaborates two chemoattractants, N-acetyl-pro-gly-pro and N-methyl-pro-gly-pro, which result directly from hydrolysis of protein. Initial efforts will center on the synthesis of other small peptides which might act as receptor antagonists, thereby inhibiting chemotaxis by blocking the receptor site on the PMN membrane. An alternate approach will identify low energy conformations of N-acetyl-pro-gly-pro and N-methyl-pro-gly-pro using NMR and computer modeling. These studies will lead to inhibitors that will bind to both chemoattractants. Suitable inhibitor drugs will be chosen from a library of known compounds. Candidate inhibitors will be screened for toxicity and inhibition of PMNs in the in vitro polarization assay. Successful inhibitor will then be used in a battery of in vivo tests for effectivity. The effect of inhibitors will be tested by intracorneal injections using PMN invasion as a histological yardstick. The inhibitor will be used alone and in conjunction with citrate and ascorbate in the alkali-injured eye.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
7R01EY004716-15
Application #
6216358
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Fisher, Richard S
Project Start
1982-07-01
Project End
2000-06-30
Budget Start
1999-12-23
Budget End
2000-06-30
Support Year
15
Fiscal Year
2000
Total Cost
$46,715
Indirect Cost
Name
Alabama Eye Bank
Department
Type
DUNS #
City
Birmingham
State
AL
Country
United States
Zip Code
35209
Pfister, Roswell R; Sommers, Charnell Inglis (2006) L-arginine-threonine-arginine (RTR) tetramer peptide inhibits ulceration in the alkali-injured rabbit cornea. Cornea 25:1187-92
Pfister, Roswell R; Sommers, Charnell Inglis (2005) Fibrin sealant in corneal stem cell transplantation. Cornea 24:593-8
Pfister, Roswell R (2004) Permanent corneal edema resulting from the treatment of PTK corneal haze with mitomycin: a case report. Cornea 23:744-7
Haddox, J L; Pfister, R R; Sommers, C I et al. (2001) Inhibitory effect of a complementary peptide on ulceration in the alkali-injured rabbit cornea. Invest Ophthalmol Vis Sci 42:2769-75
Lee, Y C; Jackson, P L; Jablonsky, M J et al. (2001) NMR conformational analysis of cis and trans proline isomers in the neutrophil chemoattractant, N-acetyl-proline-glycine-proline. Biopolymers 58:548-61
Pfister, R R; Haddox, J L; Blalock, J E et al. (2000) Synthetic complementary peptides inhibit a neutrophil chemoattractant found in the alkali-injured cornea. Cornea 19:384-9
Haddox, J L; Pfister, R R; Muccio, D D et al. (1999) Bioactivity of peptide analogs of the neutrophil chemoattractant, N-acetyl-proline-glycine-proline. Invest Ophthalmol Vis Sci 40:2427-9
Pfister, R R; Haddox, J L; Sommers, C I (1998) Injection of chemoattractants into normal cornea: a model of inflammation after alkali injury. Invest Ophthalmol Vis Sci 39:1744-50
Haddox, J L; Pfister, R R; Daniel, R L et al. (1997) A new classification system predicting keratomalacia after trauma in vitamin A deficiency: sodium citrate does not prevent disease progression. Cornea 16:472-9
Jagadeesh, B; Wheat, H S; Kontsevich, L L et al. (1997) Direction selectivity of synaptic potentials in simple cells of the cat visual cortex. J Neurophysiol 78:2772-89

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