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。糖尿病患者 导致视网膜血管变性的代谢损伤被认为涉及初始内皮细胞 由于低度慢性炎症造成的损害；然后由于受损而得不到充分修复 骨髓源性内皮祖细胞的可用性和功能。我们之前已经 证明伴有EPC功能障碍的骨髓病理是视网膜病变的先兆和必要条件 糖尿病中的血管变性。我们提出了一种分子代谢链接，连接了两个初始的 视网膜和功能障碍的内皮祖细胞的炎症涉及下调？-3多不饱和脂肪 酸性物质(PUFA)伴随着鞘脂信号中心酶ACID的激活 鞘磷脂酶(ASM)。 我们最近的研究表明，3-PUFA总量显著下降，特别是DHA 再加上糖尿病视网膜的炎性变化增加。DHA补充剂纠正了 糖尿病导致内皮祖细胞迁移和增殖减少，并预防糖尿病视网膜 炎症和视网膜血管丢失。这些发现与其他显示出有效抗炎作用的研究相吻合。 Omega-3多不饱和脂肪酸的性质。 鞘脂代谢失调被认为是胰岛素抵抗、肥胖的主要原因。 和炎症。我们鉴定了ASM的激活，这种酶将鞘磷脂转化为 炎症和促凋亡神经酰胺作为糖尿病激活内皮祖细胞和视网膜的关键成分 脉管系统。我们发现，补充DHA逆转了糖尿病内皮细胞ASM活性的增加和 视网膜内皮细胞。在视网膜病变模型中，ASM-/-动物免受血管变性的影响。 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 视网膜病变：1)防止视网膜内皮细胞激活和随后的损害；以及2)通过 通过纠正骨髓源性内皮祖细胞的功能来促进视网膜血管修复。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的ASM活性和 骨髓来源的内皮祖细胞。 这一假设将在两个具体目标上得到检验。目标1将针对特定于视网膜内皮细胞 效果和目标2将阐述ASM在糖尿病中对EPC的特定影响。建议的研究将评估 ASM作为治疗糖尿病视网膜病变的靶点的潜力。此外，我们还将确定 可通过视网膜特异性和骨髓特异性抑制ASM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.