The Role of Glycosphingolipids in Diabetic Retinopathy

描述(申请人提供)：糖尿病视网膜病变是糖尿病的一种使人衰弱的并发症，也是导致视力丧失的主要原因；然而，导致视力丧失的基本机制尚不清楚。在我们之前资助的R03拨款中，我们假设鞘磷脂代谢改变有助于糖尿病并发症，包括视网膜内的神经细胞凋亡。我们现在已经发表了糖鞘糖脂代谢异常可能导致糖尿病的代谢应激，恢复正常鞘磷脂代谢的治疗策略可能是治疗糖尿病视网膜病变的可行方法。具体地说，我们发表的和初步的数据表明，葡萄糖神经酰胺在体内糖尿病视网膜内积聚，抑制葡萄糖神经酰胺合成酶可以改善高血糖条件下的胰岛素敏感性，并减少炎性细胞因子诱导的视网膜神经细胞死亡。在目前的提案中，我们将这些观察扩展到更多的机械性研究。我们现在假设，高血糖和/或炎症直接调节葡萄糖神经酰胺合成酶的活性，导致葡萄糖神经酰胺的积聚。我们还假设，以葡萄糖神经酰胺合成酶为靶点的药物可能对糖尿病视网膜病变有治疗作用。公共卫生相关性：糖尿病视网膜病变的潜在原因尚不清楚。我们采用了脂质组学，一种复杂的质谱学策略，来量化糖尿病视网膜内的脂质代谢物的质量。初步和已发表的数据已经确定了1型糖尿病模型中糖鞘糖脂代谢功能障碍。我们研究的临床意义在于，这些脂类研究已经确定葡萄糖神经酰胺合成酶是糖尿病并发症的“可用药”靶点。

DESCRIPTION (provided by applicant): Diabetic retinopathy is a debilitating complication of diabetes and a leading cause of vision loss; however the fundamental mechanisms contributing to vision loss remain undefined. In our previously funded R03 grant, we hypothesized that altered sphingolipid metabolism contributes to diabetic complications including neuronal apoptosis within the retina. We have now published that dysfunctional glycosphingolipid metabolism may contribute to metabolic stress in diabetes and therapeutic strategies to restore normal sphingolipid metabolism may be a viable approach for treatment of diabetic retinopathy. Specifically, our published and preliminary data demonstrate that glucosylceramide accumulates within diabetic retinas in vivo and that inhibition of glucosylceramide synthase improves insulin sensitivity under hyperglycemic conditions and diminishes inflammatory cytokine-induced retinal neuronal cell death. In the present proposal, we extend these observations to more mechanistic studies. We now hypothesize that hyperglycemia and/or inflammation directly regulate glucosylceramide synthase activity, resulting in accumulation of glucosylceramides. We also hypothesize that pharmacologically targeting glucosylceramide synthase may be therapeutic for diabetic retinopathy. PUBLIC HEALTH RELEVANCE: The underlying cause of diabetic retinopathy is still unknown. We have employed lipidomics, a sophisticated mass spectroscopy strategy, to quantify the mass of lipid metabolites within the diabetic retina. Preliminary and published data have identified dysfunctional glycosphingolipid metabolism in models of Type 1 diabetes. The clinical relevance of our studies is that these lipidomic studies have identified glucosylceramide synthase as a "drugable" target for diabetic complications.