Project 173251

Diabetic retinopathy (DR) is the most common complication of diabetes, afflicting over 90% of persons with this disease and ultimately leads to blindness. Characterized by an initial phase of vascular death, followed by deregulated neovascularization, DR presents inflammatory components. Relevantly, lipid (fat) based molecules act as effectors of inflammation and angiogenesis (new vessel formation). Particularly potent are certain long chain polyunsaturated fatty acids (LCPUFAs) such as the Omega-6, which once metabolized by the cyclooxygenase (COX) enzyme, generate pro-inflammatory/ pro-angiogenic mediators. Conversely, an anti-inflammatory and anti-angiogenic influence is found with intake of Omega-3-LCPUFAs. As LCPUFA tissue status is modified by and dependent on dietary intake, these nutrients are reasonable choices for interventions to prevent DR with foods that are not usually consumed in the Western diet. The proposed study is designed to: i) Evaluate the beneficial effects of diets rich in Omega-3 LCPUFA versus those rich in Omega-6 LCPUFA on DR outcome in a mouse model of DR. COX inhibition will be investigated in conjunction with above-mentioned diets. ii) Map out mechanisms behind DR by determining for each treatment, the gene expression profile of specific factors related to lipid metabolism, inflammation and angiogenesis. iii) Predict other complementary pharmacological interventions by defining molecular pathways involved in DR and determining if they are suppressed by Omega-3 LCPUFA rich diets. Angiogenic pathways against which drugs exist (TNFa, iNOS, VEGF, and MMP) will be tested. We anticipate establishing the approach of lipid intervention in DR and finding new lipid-based compounds as surrogate markers of disease. The potential impact of this work on DR is great since nutritional interventions are safe, inexpensive and readily put into practice.