Dyslipidemia represents a prominent metabolic disorder of diabetes, however the role of the dyslipidemia in the development of diabetic retinopathy has not been studied. The retina has a very specific fatty acid profile and metabolism, different from the rest of the body. The effect of diabetes on retinal specific fatty acid metabolism and diabetes induced fatty acid profile changes is not established. Since n3 and n6 polyunsaturated fatty acids (PUFA) are known modulators of immune function and inflammation and diabetic retinopathy is proposed to be initiated by low grade inflammatory conditions, we propose the following hypothesis. The changes in fatty acid profile in diabetes are expected to predispose the retina to inflammation and be an initiating factor of the pro-inflammatory changes in the diabetic retina. To test this hypothesis the following Specific Aims will be addressed using both in vivo and in vitro models: ? ? 1) To characterize and compare the fatty acid profiles of type 1 and type 2 diabetic rat models and nondiabetic control rats fed a diet rich in either n3 or n6 PUFA. To determine the effect of the n3 and n6 PUFA rich diets on the early inflammatory changes and on the development of retinopathy in diabetic rats. ? ? 2) To determine the contribution of three major pathways (a) production of oxidized lipids; (b) regulation of transcription factors; and (c) modification of lipid raft structure and/or components to n3 and n6 PUFA regulation of basal and cytokine induced ICAM-1 and VCAM-1 expression and leukocyte adhesion using primary cultures of human retinal cells as a model. ? ? The outcome of this work will lead to a better understanding of the role of pro-inflammatory and anti-inflammatory effects of fatty acids in the onset and progression of diabetic retinopathy and will provide information on specific interventional strategies. ? ?
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