Rod outer segments (ROS) contain the highest levels of polyunsaturated fatty acids (PUFA) of any membrane in the body. Many studies have shown that the major PUFA in ROS, docosahexaenoic acid (22:6 omega 3), is important to the normal function of the retina. Dietary deprivation of its essential precursors leads to changes in the electroretinogram (ERG) in rats, primates, and premature human infants; visual acuity in primates; and brightness discrimination learning in rats. Humans, dogs, and cats with inherited retinal degenerations have lower plasma levels of 22:6 omega 3 than controls. Rats with elevated levels of 22:6 omega 3 in their retinas are more susceptible to light damage, while dietary restriction of 22:6 omega 3 or its precursors protects against light damage. Acute light damage causes a loss of 22:6 omega 3 in ROS, suggesting peroxidation of 22:6 omega 3 may be a causal factor in light damage. Clearly, the retinal degeneration that follows intravitreal injection of Fe 2+ is due to peroxidation of 22:6 omega 3. Attempts to alter the 22:6 omega 3 level in rat ROS through dietary deprivation results in only minor changes in levels of 22:6 omega 3, under conditions where most other body organs show dramatic changes. However, rats raised in different levels of cyclic light show large changes in ROS 22:6 omega 3 levels. These unique features of 22:6 omega 3 in the retina, which are discussed throughout the proposal, suggest that this fatty acid is important to the normal structure and function of the retina. Furthermore, the suggestion of a defect in 22:6 omega 3 metabolism in inherited retinal degenerations makes it even more important that the metabolism of this fatty acid be studied. The long-term goal of this research project is to determine the function of 22:6 omega 3 in normal and diseased retinas.
The specific aims of this five-year proposal are: 1) to study the role of 22:6 omega 3 in the inherited retinal degenerations in the miniature poodle and Abyssinian cat, 2) to determine the mechanism of conservation of 22:6 omega 3 in the rat retina during essential fatty acid deficiency, 3) to determine the role of 22:6 omega 3 in the biochemical adaptation of the rat retina to cyclic light, as related to susceptibility to acute light damage, as well as to damage by chronic exposure to cyclic light of different intensities, 4) to study the effects of chronic administration of antioxidants on the susceptibility of the retina to damage by acute constant light challenge, as well as to damage by chronic exposure to cyclic light of different intensities, and 5) to determine the site of elongation and desaturation (retinal vs. extraretinal) of 22:6 omega 3 and to study these metabolic processes. To achieve these goals, a series of in vivo and in vitro experiments are proposed in which the metabolism of 22:6 omega 3 will be studied in detail. Each step of the elongation and desaturation pathways in the formation of 22:6 omega 3 will be tested in retinas and liver homogenates of dogs and cats with inherited retinal degeneration. Rats will be raised on omega3- and/or omega6-deficient diets and injected intravitreally with lipid precursors in order to study the biochemical mechanisms of conservation of 22:6 omega 3. Similar groups of animals will be raised in bright or dim cyclic light to determine if elevated dietary PUFA levels make them more susceptible to light damage. The results of these studies will give a better understanding of the metabolism of 22:6 omega 3 in the retina and perhaps shed some light on the role of this fatty acid in retinal degenerations.
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