The influence of the protease inhibitor cystatin C on the occurrence of age-related macular degeneratin: evaluation of secretion by RPE cells and of possible mechanisms for its inhibition

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We have previously shown that CST3 is genetically associated with exudative age-related macular degeneration (ARMD). In this study, we intend to correlate between the CST3 genotype and the levels of gene expression, as well as posttranslational processing of the CST3 gene product, the cysteine protease inhibitor cystatin C in retinal pigment epithelial (RPE) cells. Cystatin C is a strog inhibitor of cathepsin S, one of the most important proteases in RPE cells; it is involved in the proteolytic metabolic pathways of these cells. The exact ways by which genotype can influence the phenotype at the cellular level are unknown. This study was designed to determine possible influences of cystatin C on proteases including cathepsin S which has a high activity in RPE cells. By using the RPE tissue culture model, we will test possible associations of the allelic variants with advanced exudative ARMD, and thus address the molecular basis of the resulting phenotype. To pursue these objectives, we habe established a DNA bank derived from of l67 patients with advanced exudative ARMD and from 268 control subjects. Moreover, the methods of culturing RPE cells are established in our laboratory.