Macular degeneration associated with age and drusen is the leading cause of severe visual loss among older individuals in the United States and other countries. Its cause and treatment are unknown. Clinicopathologic studies have associated abnormalities of Bruch's membrane with the disease. Recently, in one group of patients, orally administered elemental zinc retarded the visual loss associated with macular degeneration. Zinc is particularly plentiful in the chorioretinal complex. Preliminary studies have shown it to be taken up in a facilitated fashion by the pigment epithelium, although the exact mechanism is unknown. The mechanism and kinetics of zinc uptake by the human retinal pigment epithelium using both native tissue and cultured cell layers will be investigated using radioactive zinc as a probe in experiments with and without substances that block, stimulate, reduce, or compete for uptake. Because zinc is a cofactor of enzymes involved in the synthesis of extracellular matrix molecules, particularly glycoconjugates associated with Bruch's membrane, we will investigate the effects of different zinc concentrations on the production of these molecules. Some extracellular matrix molecules play important roles in the normal adhesion of the pigment epithelium to Bruch's membrane, which is interrupted by drusen, pigment epithelial detachment, and other changes of macular degeneration. Using differential extraction and affinity chromatographic procedures we plan to investigate the interactive properties of glycoconjugates with other structural macromolecules of Bruch's membrane. Zinc is also a cofactor for enzymes involved in the maintenance of cellular integrity, such as superoxide dismustase. The effects of different concentrations of zinc on the activity of this enzyme in native and cultured pigment epithelium will be studied. These studies should improve our understanding of the role of zinc in the metabolism of the normal retinal pigment epithelium with particular respect to the synthesis of extracellular matrix molecules and transepithelial transport, and should prove relevant to such clinically important conditions as macular degeneration.
