Julia Busik, Ph.D.
Biomedical Physical Sciences Building
567 Wilson Rd Rm 3178
Department of Physiology
Michigan State University
East Lansing, MI 48824
Diabetic retinopathy is one of the most disabling diabetic complications with both type 1 and type 2 diabetic patients being affected by the disease. Diabetic retinopathy is a leading cause of blindness in adults. Despite the progress made in the last decade in understanding of the molecular mechanisms of the disease, diabetic retinopathy is still neither preventable norcurable. Early diabetic retinopathy has been recognized as a low-grade chronic inflammatory disease involving induction of specific adhesion molecules followed by increased leukocyte attachment and transmigration into the vascular intima (Fig. 1). The individual molecular steps leading to inflammation in the retina are not well resolved, but likely involve hyperglycemia and dyslipidemia associated with diabetes mellitus. We have demonstrated that n6 fatty acids (linoleic18:2n6 and arachidonic20:4n6 ) have a pro-inflammatory effect and the major n3 polyunsaturated fatty acid (PUFA) in the retina, docosahexaenoic acid (DHA22:6n3), has a pronounced anti-inflammatory effect on human Retinal Vascular Endothelial cells. The ongoing study in my laboratory also demonstrated that diabetes induced a decrease in DHA22:6n3 in the plasma and the retina with a shift toward a higher n6 to n3 PUFA ratio in animal model. The hypothesis ofthis study is that the diabetes induced decrease in DHA 22:6n3 with a concomitant increase in the n6 to n3 PUFA ratio promotes basal and cytokine induced adhesion molecules expression, leukocyte adhesion and, finally, development of the anatomic lesions of diabetic retinopathy (Fig. 2).
Two major approaches are used in the laboratory. First, we use animal models of type 1 and type 2 diabetes to determine the changes in plasma and retinal lipid profiles induced by the disease. We then apply dietary supplementation with n3 fatty acids to alter diabetes induced changes in the fatty acid profiles as a route to prevent or reduce the development of diabetic retinopathy.
Animal studies provide critical in vivo information on dyslipidemia induced changes in the diabetic retina. To determine the precise retinal specific biochemical mechanisms of the diabetes induced changes we use primary cultures of human Retinal Vascular Endothelial (hRVE) cells as a model. Three major pathways are studied in these cells (a) production of oxidized lipids; (b) regulation of transcription factors; and (c) modification of lipid raft structure and/or components by n3 and n6 fatty acids as a route of regulation of basal and cytokine induced adhesion molecule expression and subsequent leukocyte adhesion.
Bhatwadekar, A.D., Y. Yan, X. Qi, J.S. Thinschmidt, M.B. Neu, S. Li Calzi, L.C. Shaw, J.M. Dominiguez, J.V. Busik, C. Lee, M.E. Boulton, and M.B. Grant, Per2 Mutation Recapitulates the Vascular Phenotype of Diabetes in the Retina and Bone Marrow. Diabetes, 2012.
Busik, J.V., W.J. Esselman, and G.E. Reid, Examining the role of lipid mediators in diabetic retinopathy. Clinical Lipidology, 2012. 7(6): p. 661-675.
Ho, N.T., K. Furge, W. Fu, J. Busik, S.K. Khoo, Q. Lu, M. Lenski, J. Wirth, E. Hurvitz, N. Dodge, J. Resau, and N. Paneth, Gene expression in archived newborn blood spots distinguishes infants who will later develop cerebral palsy from matched controls. Pediatric Research, 2012.
Resau, J.H., N.T. Ho, K. Dykema, M.S. Faber, J.V. Busik, R.Z. Nickolov, K.A. Furge, N. Paneth, S. Jewell, and S.K. Khoo, Evaluation of Sex-Specific Gene Expression in Archived Dried Blood Spots (DBS). Int J Mol Sci, 2012. 13(8): p. 9599-608.
Bhatwadekar, A.D., Y. Yan, X. Qi, J.S. Thinschmidt, M.B. Neu, S. Li Calzi, L.C. Shaw, J.M. Dominiguez, J.V. Busik, C. Lee, M.E. Boulton, and M.B. Grant, Per2 mutation recapitulates the vascular phenotype of diabetes in the retina and bone marrow. Diabetes, 2013. 62(1): p. 273-82.
Tikhonenko, M., T.A. Lydic, M. Opreanu, S. Li Calzi, S. Bozack, K.M. McSorley, A.L. Sochacki, M.S. Faber, S. Hazra, S. Duclos, D. Guberski, G.E. Reid, M.B. Grant, and J.V. Busik, N-3 polyunsaturated Fatty acids prevent diabetic retinopathy by inhibition of retinal vascular damage and enhanced endothelial progenitor cell reparative function. PLoS ONE, 2013. 8(1): p. e55177.
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