This project will employ human tissues, and models of human disease in the rat, where appropriate, in studies related to several clinically important disorders. The planned studies will deal with: the pathogenesis of retinal neovascularization in a retinal-dystrophic rat model; events in the retinal pigment epithelium (RPE) of donor eyes from aging humans that may be related to the pathogenesis of age-related macular degeneration (ARMD); and the effects of potentially therapeutic drugs on an animal model (the long-term galactosemic rat) that has been reported to develop lesions identical to those of diabetic retinopathy. In pigmented Royal College of Surgeons (RCS) retinal-dystrophic rats, we will use fluorescein angiography to define the natural history of the neovascular process, and we will integrate these findings with autoradiographic and qualitative and quantitative electron microscopic immunocytochemical studies of cell proliferation, growth factors, extracellular matrix molecules, and markers for specific cell types to define the cell biology of the process with reference to a specific hypothesis of the pathogenesis of retinal neovascularization. In human donor eyes, we will use histochemical and immunocytochemical methods for qualitative and quantitative evaluation of specific growth factors, extracellular matrix molecules, cytoplasmic retinaldehyde-binding protein, sodium-potassium activated adenosine triphosphatase, and superoxide dismutase. We will attempt to correlate these findings with epidemiologic data including the age, race, and iris color of the donor, which appear to be relevant to the risk of developing ARMD. Results of this study may identify cellular processes that are closely related to the pathogenesis of this disease. Finally, we will follow rats fed a diet containing 50% by weight galactose for up to 30 months to confirm the development of a diabetic-like retinopathy that has been reported by other investigators, but which we have not observed in rats fed 30% galactose for up to 21 months. In some rats, we will intervene at the outset of the diet, and in others after 6 and 12 months of the diet with two potential therapeutic agents, the aldose reductase inhibitor tolrestat and the protein glycation inhibitor aminoguanidine to determine if these interventions are effective and is so, whether time of administration is relevant, in blocking the lesions that may develop. Retinal vessels of the animals will be studied by autoradiography, quantitative electron microscopic immunocytochemistry, and electron microscopic morphometry to investigate vascular cell mitosis, basement membrane thickening, and the role of basement membrane molecules and growth factors in the development of the presumed retinopathy.
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