Dyslipidemia and retinal endothelial cell dysfunction

描述(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以毛细血管闭塞、微动脉瘤、周细胞选择性丢失、无细胞毛细血管、基底膜肥大、血管生成和新生血管为特征的视网膜微血管病变。虽然视网膜微血管损伤的最初决定因素尚不清楚，但最近的研究表明，糖尿病视网膜病变是一种低级别的慢性炎症性疾病。因此，最近的研究记录了白细胞附着和移行到血管内膜的增加。白细胞与内皮细胞的黏附增加可能涉及到诱导特定的黏附分子，如ICAM-1。升高细胞黏附分子的因素尚未明确，但可能与糖尿病相关的高血糖和血脂异常有关。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细胞(HRVE)会导致ICAM-1的诱导，以及几个信号通路的改变。 我们假设，hRVE细胞暴露于特定的脂肪酸会导致特定的生物活性脂质的形成，从而导致细胞信号和基因表达的改变，并导致黏附分子和白细胞黏附的增加。为了验证这一假说，提出了以下目标：1)评估脂肪酸和葡萄糖对hRVE细胞黏附分子表达和细胞信号转导的影响。2)将黏附分子表达和细胞信号的变化与特定生物活性脂类的产生联系起来。 这项工作的结果将有助于更好地理解糖尿病血脂异常如何导致hRVE细胞表型改变以及糖尿病视网膜病变的发生和发展。

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.