Dyslipidemia and Diabetic Retinopathy

糖尿病视网膜病变是一种威胁视力的疾病，没有有效的治疗选择。糖尿病 导致视网膜血管变性的代谢损伤被认为涉及最初的内皮细胞 由于低度慢性炎症造成的损伤;然后由于受损而无法充分修复 骨髓来源的内皮祖细胞（EPCs）的可用性和功能。我们先前已经 研究表明，骨髓病理与EPC功能障碍之前，是必要的视网膜病变， 糖尿病的血管变性我们认为，一个分子代谢环节，连接两个初始的 视网膜炎症和EPCs功能障碍涉及到<$-3多不饱和脂肪酸的下调， 酸（PUFA）与鞘脂信号传导的中心酶，酸 鞘磷脂酶（ASM）。 我们最近的研究表明，总的3-PUFAs，特别是DHA，这是紧密 伴随着糖尿病视网膜的炎症变化增加。DHA补充剂纠正了 糖尿病诱导EPCs迁移和增殖减少，并阻止糖尿病诱导的视网膜病变。 炎症和视网膜血管损失。这些发现与其他研究结果相吻合，这些研究表明， omega-3 PUFA的特性。 鞘脂代谢的失调被认为在胰岛素抵抗、肥胖和肥胖中起主要作用。 和炎症。我们确定了ASM的激活，这种酶将鞘磷脂转化为前体， 炎症和促凋亡神经酰胺，作为糖尿病激活EPCs和视网膜的关键因素， 脉管系统我们发现，补充DHA逆转了糖尿病EPCs中ASM活性的增加， 视网膜内皮细胞ASM-/-动物在视网膜病变模型中免受血管变性。 基于这些数据，我们假设补充DHA可以改善糖尿病患者的预后。 通过：1）防止视网膜中的内皮细胞活化和随后的损伤;和2）通过 通过纠正骨髓来源的EPCs的功能来改善视网膜血管修复。我们建议 DHA的有益作用至少部分是由于抑制视网膜内皮细胞中的ASM活性， 骨髓来源的EPCs。 这一假设将在两个具体目标中得到检验。目标1将解决视网膜内皮细胞特异性 目的2将解决ASM在糖尿病中的EPC特异性作用。拟议的研究将评估 ASM作为糖尿病视网膜病变治疗靶点的潜力。此外，我们将确定 可以通过ASM视网膜特异性和骨髓特异性抑制实现治疗潜力， 确定最佳治疗策略。

Diabetic retinopathy is a sight threatening disease without effective therapeutic options. The diabetic metabolic insult leading to retinal vascular degeneration is proposed to involve the initial endothelial cell damage due to low-grade chronic inflammation; that is then inadequately repaired due to compromised availability and functionality of bone marrow derived endothelial progenitor cells (EPCs). We have previously demonstrated that bone marrow pathology with EPC dysfunction precedes and is necessary for retinal vascular degeneration in diabetes. We propose that a molecular metabolic link connecting both the initial inflammation in the retina and the dysfunctional EPCs involves downregulation of ¿-3 polyunsaturated fatty acids (PUFA) with concomitant activation of the central enzyme of sphingolipid signaling, acid sphingomyelinase (ASM). Our recent study demonstrated a significant decrease in total 3-PUFAs, especially DHA, that was tightly coupled with increased inflammatory changes in the diabetic retina. DHA supplementation corrected the diabetes induced decrease in migration and proliferation in EPCs, and prevented diabetes induced retinal inflammation and retinal vessel loss. These findings fit with other studies showing potent anti-inflammatory properties of omega-3 PUFAs. Dysregulation of sphingolipid metabolism is believed to play a major role in insulin resistance, obesity and inflammation. We identified activation of ASM, the enzyme converting sphingomyelin into pro- inflammatory and pro-apoptotic ceramide, as a key element activated by diabetes in both EPCs and retinal vasculature. We found that DHA supplementation reversed increases in ASM activity in diabetic EPCs and retinal endothelial cells. ASM-/- animals were protected from vascular degeneration in retinopathy models. Based on these data we hypothesize that DHA supplementation improves the outcomes of diabetic retinopathy by: 1) preventing endothelial cell activation and subsequent damage in the retina; and 2) through improving retinal vascular repair by correcting the function of bone marrow derived EPCs. We propose that the beneficial effects of DHA are due, at least in part, to inhibition of ASM activity in retinal endothelial cells and bone marrow derived EPCs. This hypothesis will be tested in two Specific Aims. Aim 1 will address retinal endothelial specific effects and Aim 2 will address EPC specific effects of ASM in diabetes. The proposed studies will assess the potential of ASM as a target for the treatment of diabetic retinopathy. Moreover, we will identify the extend of therapeutic potential that can be achieve by retinal-specific and bone-marrow specific inhibition of ASM to determine the best therapeutic strategies.