TURNOVER OF SUBSTANCES IN THE OUTFLOW PATHWAY OF THE EYE

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The precise mechanism by which aqueous outflow is regulated is not known but interactions between the cells of the trabecular meshwork, their underlying collagen beams and other extracellular substances (including glycosaminoglycans) may play an important role. These cells, given their phagocytic properties, are capable of removing debris or particles in the anterior chamber that become trapped in the pores of the meshwork, thereby affecting intraocular pressure. A change in the metabolic state of these cells due to the effects of aging, drugs, hormones, environment or other influences may lead to an altered turnover of endogenous and foreign substances and decrease aqueous outflow facility. The goal of the proposed research is to evaluate the role of phagosome/lysosome-mediated events of the trabecular cells in regulating agueous outflow facility. Trabecular cells obtained from human, monkey and bovine eyes will be maintained in culture. The rate of phagocytosis by these cells of various radiolabeled particles including lens material, red blood cells and protein-laden latex spheres will be determined. The trabecular cell surface components involved in particle recognition and ingestin will be identified by cell surface radiolabeling and by radio-iodinated and fluorscein-labeled lectin binding studies. Chemical modification of the trabecular cell surface or the addition of various substances to the trabecular cells prior to or concomitant with phagocytosis may provide insights regarding factors that effect particle recognition and ingestion. The kinetics of particle degradation by the lysosomal enzymes will be examined as well as the effect of phagocytosis on the synthesis and release of these enzymes from the cells. The lysosomal enzymes may also play an important role in the turnover of material endogenous to the trabecular meshwork and thus contribute to the regulation of intraocular pressure. Enzyme activities and biochemical properties of lysosomal enzymes from human trabecular tissue excised from normal and glaucomatous eyes will be compared. In addition, studies are proposed to investigate the biochemical properties of lysosomal enzymes in trabecular cells and to determine factors that influence their cellular and extracellular localization. The mechanism by which these enzymes are targeted to lysosomes and extracellular fluids will be investigated by determining the types of carbohydrate structure on the lysosomal enzymes from trabecular cells. The localization and biochemical properties of lysosomal enzymes in cultured trabecular cells will also be evaluated after treatment with experimental agents that are known to affect intraocular pressure.