A large number of studies have shown that certain lipids, particularly docosahexaenoic acid (22:6n-3, DHA), play an important role in the retina. 1) Recent epidemiological studies have implicated n-3 fatty acids as a positive risk factor in age-related macular degeneration. 2) Patients with retinitis pigmentosa (RP) and some animal models of RP have lower blood levels of 22:6n-3; rod outer segments from animal models of human RP have less 22:6n-3 than controls, even after supplementation with n-3 fatty acids. 3) A mutation of a gene in Stargardt 3 (Stgd3) patients that encodes a protein (Elovl4) that has significant homology throughout its entire sequence to a family of proteins that function in the dongation of fatty acids. This proposal contains experiments designed to provide vital information on the role of lipids in the retinas of animal models of human retinal degenerations, utilizing a multi-disciplinary approach involving molecular biology, biochemistry, and physiology.
The Specific Aims are to: 1. Determine the role of 22:6n-3 in inherited retinal degenerations. We will test the hypothesis that the reduction of ROS 22:6n-3 in animals with inherited retinal degeneration is indicative of an underlying pathophysiology that occurs in MOST if not ALL animals with an inherited retinal degeneration. 2. Determine the metabolic function of the Elovl4 protein. Using in vivo and in vitro approaches, we will determine if the metabolic pathway encoded by the Elovl4 gene is involved in retinal lipid metabolism and how the defect leads to rod and/or cone photoreceptor cell deafly. 3. Determine the role of the Elovl6 protein in the retina. A complete structural and functional assessment of the retinas as a function of age will determine if these animals have a retinal degeneration that leads to rod and/or cone photoreceptor cell death. 4. Characterize the retinas of fat-1 mice. Transgenic mice expressing the fat-1 gene, which encodes an enzyme that converts n-6 PUFA to n-3 PUFA, have elevated n-3 PUFA in all tissues examined, including the brain (retina has not yet been studied). These mice provide a unique opportunity to study the role of 22:6n-3 in the retina.
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