These projects are designed to provide insight into the etiology and pathogenesis of hereditary retinal degeneration (rd). A new animal model will be utilized: a mutant strain of Rhode Island Red chickens in which blindness is transmitted by an autosomal recessive mode. To date we have found that the ERG response of newly hatched rd chicks is not measurable while retinal morphology appears similar to a normal chick retina whose ERG is near adult levels at the same age. After about 1 week post-hatching, the rd retinas degenerate. Under the present grant we will describe the pathogenesis and determine the etiology of blindness and photoreceptor (PR) cell degeneration in this model. The temporal and spatial patterns of cell death will be analyzed by light and electron microscopy. Retinal function prior to hatching will be assessed by ERG and measurement of the pupillary reflex. Affected retinas will be analyzed for the presence of normal visual pigments and their recycling in response to light. Protein and RNA synthesis will be assayed in normal and rd retinas and compared. Metabolic processes in PR cells in this non-electrical retina will be studied: outer segment disc assembly, migration, shedding, phagocytosis and degradation will be tested by autoradiography on incorporation of 3H-leucine in specimens. Ability of retinal ganglion cells to synthesize and transport proteins will be measured by tracing anterograde transport of 3H-proline and the retrograde transport of horseradish peroxidase. We will determine to what extent blindness and PR degeneration might be caused by systemic agents by 2 methods: 1 by grafting optic cups between rd and normal embryos at an early stage and later testing pupillary reflex, ERG and morphology; and 2 by culturing rd eyecups in media containing serum and extracts from normal chicks while normal eyecups are cultured in rd serum and extracts--subsequently morphology will be examined. Brains of rd chicks will be examined for normalcy of visual center histology as well as for target areas of retinal ganglion cells. Finally, the role of light in promoting or retarding the disease will be assessed. By probing these areas, we hope to elucidate some of the questions associated with human retinal degenerations and contribute to finding agents or manipulations that may some day arrest or prevent these debilitating diseases from occurring.
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