The Role of Ceramide in Diabetic Retinopathy

描述（由申请人提供）：糖尿病视网膜病变的特征在于血管通透性和血管生成改变，以及胰岛素信号传导受损和导致视网膜神经元凋亡。 该项目是基于一个范式转换假设，表明糖尿病的潜在异常是棕榈酸酯在外周非脂肪组织（包括视网膜）中不适当地代谢为生物活性神经酰胺。 这一假设的一个推论是，胰岛素抵抗是神经酰胺从头合成增加的结果，导致胰岛素依赖性AKT信号转导的破坏。 本提案的总体假设是，糖尿病中神经酰胺代谢的改变导致膜微区（筏）内的胰岛素受体功能障碍。 我们的初步数据表明，C16-神经酰胺选择性地积累在糖尿病视网膜，棕榈酸诱导的从头合成的可能结果。此外，外源性神经酰胺模拟糖尿病诱导的胰岛素抵抗，如AKT活性和细胞活力降低所证明的。 我们特别假设，神经酰胺积累在脂质微结构域导致减少胰岛素受体信号作为改变与信号元件或支架蛋白的相互作用的结果。 我们将使用复杂的生化物质，分子和遗传模型来证明神经酰胺代谢的改变有助于减少视网膜中的胰岛素信号。 这些研究有可能将神经酰胺蓄积确定为可以治疗或分子操纵的靶点。

DESCRIPTION (provided by applicant): Diabetic retinopathy is characterized by altered vascular permeability and angiogenesis, as well as impaired insulin signaling and resulting apoptosis in retinal neurons. The project is based upon a paradigm shifting postulate suggesting that the underlying abnormality in diabetes is the inappropriate metabolism of palmitate into bioactive ceramide in peripheral non-adipose tissues, including the retina. A corollary to this postulate is that insulin-resistance is a consequence of augmented de novo ceramide synthesis, leading to disruption of insulin-dependent AKT signaling. The overall hypothesis of the present proposal is that altered ceramide metabolism in diabetes leads to insulin receptor dysfunction within membrane microdomains (rafts). Our preliminary data suggest that C16-ceramide selectively accumulates in diabetic retinas, a possible result of palmitic acid-induced de novo synthesis. In addition, exogenous ceramide mimics diabetic-induced insulin resistance, as evidenced by decreased AKT activity and cell viability. We specifically hypothesize that ceramide accumulation within lipid microdomains leads to diminished insulin receptor signaling as a consequence of altered interactions with signaling elements or scaffold proteins. We will use sophisticated biochemicals, molecular and genetic models to demonstrate that altered ceramide metabolism contributes to reduced insulin signaling in the retina. These studies have the potential to identify ceramide accumulation as a target that can be therapeutically or molecularly manipulated.