Dyslipidemia and Diabetic Retinopathy

描述(申请人提供)：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。导致视网膜血管变性的糖尿病代谢损伤被认为是由低度慢性炎症引起的初始内皮细胞损伤，然后由于骨髓来源的内皮祖细胞(EPC)的可用性和功能受损而得不到充分修复。我们先前已经证明，伴有内皮祖细胞功能障碍的骨髓病理是糖尿病视网膜血管变性的先兆和必要条件。我们认为，连接视网膜初始炎症和功能障碍的内皮祖细胞的分子代谢链涉及β-3多不饱和脂肪酸(PUFA)的下调，同时伴随着鞘磷脂信号转导的中心酶酸性鞘磷脂酶(ASM)的激活。我们最近的研究表明，糖尿病视网膜中总的3-PUFAs显著减少，尤其是DHA，这与糖尿病视网膜中炎性变化的增加密切相关。补充DHA可纠正糖尿病引起的内皮细胞迁移和增殖减少，预防糖尿病引起的视网膜炎症和视网膜血管丢失。这些发现与其他显示omega-3多不饱和脂肪酸有效抗炎特性的研究相吻合。鞘脂代谢失调被认为是胰岛素抵抗、肥胖和炎症的主要原因。我们发现ASM的激活是糖尿病激活内皮祖细胞和视网膜血管系统的关键因素。ASM是一种将鞘磷脂转化为促炎和促凋亡神经酰胺的酶。我们发现，补充DHA逆转了糖尿病内皮细胞和视网膜内皮细胞ASM活性的增加。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可通过以下方式改善糖尿病视网膜病变的结局：1)防止视网膜内皮细胞激活和随后的损害；2)通过纠正骨髓来源的内皮祖细胞的功能来改善视网膜血管修复。我们认为DHA的有益作用至少部分归因于抑制视网膜内皮细胞和骨髓源性内皮祖细胞的ASM活性。这一假设将在两个具体目标上得到检验。目标1将解决视网膜内皮细胞的特定影响，目标2将解决糖尿病时ASM对EPC的特定影响。拟议的研究将评估ASM作为治疗糖尿病视网膜病变的靶点的潜力。此外，我们将确定通过视网膜特异性和骨髓特异性抑制ASM所能达到的治疗潜力的程度，以确定最佳的治疗策略。 与公共卫生相关：鞘磷脂代谢失调正被认为是糖尿病血脂异常的重要组成部分，在胰岛素抵抗、肥胖和炎症中发挥重要作用；鞘磷脂代谢在视网膜中的作用开始显现。我们的初步研究表明，在1型和2型糖尿病动物模型中，添加富含？3多不饱和脂肪酸的饮食有效地纠正了视网膜病理，至少部分是通过抑制神经鞘磷脂途径顶端的主要酶酸性鞘磷脂酶来实现的。这项建议将解决酸性鞘磷脂酶激活在糖尿病视网膜病变发病机制中的作用，并将为这种威胁视力的疾病提供新的治疗靶点。

DESCRIPTION (provided by applicant): 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 down regulation 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 extent of therapeutic potential that can be achieved by retinal-specific and bone-marrow specific inhibition of ASM to determine the best therapeutic strategies. PUBLIC HEALTH RELEVANCE: Dysregulation of sphingolipid metabolism is becoming recognized as an important part of diabetic dyslipidemia playing a major role in insulin resistance, obesity and inflammation; and the role of sphingolipid metabolism in the retina is beginning to emerge. Our preliminary studies demonstrate that diets supplemented with ?3 PUFA- rich effectively corrected retinal pathology in both type 1 and type 2 diabetes animal models through, at least in part, inhibition of acid sphingomyelinase, the major enzyme at the top of sphingolipid pathway. This proposal will address the role of acid sphingomyelinase activation in the pathogenesis of diabetic retinopathy and will provide novel therapeutic targets for this sight threatening disease.