Dyslipidemia and retinal endothelial cell dysfunction

描述（由申请人提供）：糖尿病视网膜病变是成人失明的主要原因。糖尿病视网膜病变是一种视网膜微血管疾病，其特征在于毛细血管闭塞、微动脉瘤、周细胞、无细胞毛细血管的选择性损失、基底膜肥大、血管生成和新血管形成。虽然视网膜微血管损伤的最初决定因素还不清楚，但最近的研究表明，糖尿病视网膜病变是一种低度慢性炎症性疾病。因此，最近的研究记录了白细胞附着和迁移到血管内膜中的增加。白细胞对内皮细胞的粘附增加可能涉及特异性粘附分子如ICAM-1的诱导。升高细胞粘附分子的因素尚未明确，但可能涉及与糖尿病相关的高血糖症和血脂异常。我们的初步研究表明，用特定的脂肪酸处理人视网膜血管内皮（hRVE）细胞导致ICAM-1的诱导，以及几个信号通路的改变。 我们推测，hRVE细胞暴露于特定的脂肪酸导致形成特定的生物活性脂质，引起细胞信号传导和基因表达的改变，并导致粘附分子和白细胞附着的表达增加。为了验证这一假设，我们提出了以下目标：1）评估脂肪酸和葡萄糖对hRVE细胞粘附分子表达和细胞信号转导的影响。2)将粘附分子表达和细胞信号传导的变化与特定生物活性脂质的产生相关联。 这项工作的结果将导致更好地了解糖尿病血脂异常如何有助于改变hRVE细胞表型和糖尿病视网膜病变的发病和进展。

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.