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Julia Busik, Ph.D
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of Research Interest [PDF]
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 nor
curable. 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 of
this study is that the diabetes induced decrease in DHA22:6n3
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.
1. Chen, W., D. B. Jump, M.B. Grant, W.J. Esselman, and J.V.
Busik (2003) Dyslipidemia, but not hyperglycemia, induces inflammatory
adhesion molecules in human retinal vascular endothelial cells.
Inv. Ophthal. Vis. Sci. 44(11): 5016-22.
2. Chen, W., W. Esselman, D. Jump and J. Busik (2005) "Anti-Inflammatory
Effect of Docosahexaenoic Acid (DHA) on Cytokine Induced Adhesion
Molecule Expression in Human Retinal Vascular Endothelial Cells"
(2005) Inv. Ophthal. Vis. Sci. 46(11):4342-7
