Schutz vor oxidativem Stress in retinalen Geweben durch Tyrosinase und seiner Metaboliten in Kombination mit oraler Zinkaufnahme

• Antragsteller: Professor Dr. Ulrich Schraermeyer
• Fachliche Zuordnung: Augenheilkunde
• Förderung: Förderung von 2003 bis 2009
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 5399649

The melanin content of the eye is inversely proportional to the incidence of macular degeneration. In contrast, in healthy people the melanin level is two- to three times higher in the macular RPE and the choroid than in other areas. The risk of suffering from AMD is 40 times higher in whites than in blacks. Loss of tyrosinase and melanin is the most prominent feature of aging and causes gray hair color. Therefore, melanin or melanin producing enzymes or their metabolites seem to be involved in the pathology of AMD by protecting the RPE and the choriocapillaris from oxidative stress. However, it is believed that tyrosinase in the RPE is only expressed in prenatal periods and therefore melanogenesis is absent after birth. Recently we found that tyrosinase, the key enzyme of melanogenesis, is induced at the protein level in RPE cells by uptake of rod outer segments in vitro and in vivo. Tyrosinase was also detected within lysosomes that degrade rod outer segments (ROS). Phagocytosis of ROS induces oxidative stress to RPE cells and the phagosomes contain reactive oxygen species. In this study a high capacity adeno viral vector will be used for overexpression of tyrosinase in RPE cells of albino rats in vivo and in vitro. By this investigation we shall find out whether tyrosinase or its metabolites can support rod outer segment degradation by detoxification of reactive oxygen species in lysosomes and whether can protect RPE and choroidal cells from oxidative stress. It will also become evident whether tyrosinase activation can inhibit lipofuscin formation. A strategy is developped by which first the amount of melanin is artifically enhanced and second by substitution with Zn the intracellular concentration of Zn is augmented. Thus it will be investigated whether the protection from oxidative stress by Zn substitution is more effective in pimented than in albinotic cells.

• DFG-Verfahren: Sachbeihilfen