Dyslipidemia and retinal endothelial cell dysfunction

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Diabetic retinopathy represents the leading cause of blindness in adults. Diabetic retinopathy is a disease of the retinal microvessels characterized by capillary occlusions, microaneurysms, selective loss of pericytes, acellular capillaries, hypertrophy of the basement membrane, angiogenesis and neovascularization. While the initial determinants of retinal microvascular damage are not well understood, recent studies suggest that diabetic retinopathy is a low-grade chronic inflammatory disease. As such, recent studies document increased leukocyte attachment and transmigration into the vascular intima. The increased adherence of leukocytes to endothelial cells likely involves induction of specific adhesion molecules, such as ICAM-1. The factors elevating cellular adhesion molecules are not well defined, but likely involve hyperglycemia and dyslipidemia associated with diabetes mellitus. Our preliminary studies show that treating human retinal vascular endothelial (hRVE) cells with specific fatty acids leads to the induction of ICAM-1, as well as alterations in several signaling pathways. We hypothesize that exposure of hRVE cells to specific fatty acids leads to the formation of specific bioactive lipids that cause alterations in cell signaling and gene expression and lead to increased expression of adhesion molecules and leukocyte attachment. To test this hypothesis, the following aims are proposed: 1) To evaluate the effects of fatty acids and glucose on adhesion molecule expression and cell signaling in hRVE cells. 2) To correlate changes in adhesion molecule expression and cell signaling to the production of specific bioactive lipids. The outcome of this work will lead to a better understanding of how diabetic dyslipidemia contributes to altered hRVE cell phenotype and the onset and progression of diabetic retinopathy.