This proposal describes an innovative nutritional/pharmacological strategy to prevent proliferative retinopathy in a mouse model of disease with the expectation of a later clinical trial of patients with diabetic retinopathy (DR). DR has inflammatory and angiogenic components. We will evaluate alone and interactively the efficacy of the ?-3 long-chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid and eicosapentaenoic acid and Celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, designed to target inflammatory and angiogenic factors implicated in the pathogenesis of proliferative DR. ?-3 LCPUFAs are concentrated in the retina and the status is modifiable by and dependent on dietary intake from foods that are not consumed in all Western diets, so these lipids are reasonable choices for interventions to prevent DR. Preliminary results show COX-2 inhibitors prevent ischemia-induced retinal neovascularization and that COX-2 inhibition is synergistic with ?-3 LCPUFAs. Should Celecoxib prove to cause cardiac disease we will switch to aspirin (COX 1,2 inhibition). To determine mechanism of inhibition and to determine complementary interventions, a new technique will be used to sensitively measure small changes with treatment in absolute copy number of mRNAs of specific lipid, inflammatory and angiogenic pathways involved in disease. The panel will include (but is not limited to) COX1,2, and LOX, vascular endothelial growth factor and receptors 1,2, cell adhesion molecules (ICAM-1, CD18), matrix metalloproteinases 2,9, cytokines (TNFa, TGF?), nuclear hormone receptor (NF?B), and nitric oxide synthetase. To assess intervention and possible new surrogate markers of DR we will assess retinal and blood levels of ?-3 LCPUFAs, arachidonic acid and eicosanoids (thromboxanes, prostaglandins, leukotrienes) in mice consuming balanced, isocaloric diets with, or without ?-3 LCPUFAs. For this translational work an inter-institutional and intra-disciplinary research group has been established with experts in the fields of molecular and cellular biology and angiogenesis (L Smith, (PI), D Carper, J-Y Tsai, NEI), clinical research (E Chew, J-P SanGiovanni, NEI), nutrition and lipid biochemistry (N Salem, NIAAA, C Serhan, Harvard). If successful, this work could have a great impact on preventing proliferative DR, as the interventions are safe, inexpensive, and can be easily implemented. Preliminary results show that COX-2 inhibitors, ?-3 LCPUFAs and combination inhibit retinopathy. These studies are innovative in that: 1. they are the first to examine the effect of LCPUFAs with or without COX-2 inhibitors on DR. 2. a new technique of finding absolute copy numbers of mRNA during disease and intervention allows comparison of interventions to evaluate complementary treatments. 3. lipid analysis may yield mechanism as well as new surrogate markers of DR and risk.
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