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是血管通透性和血管生成改变，以及胰岛素信号受损和视网膜神经元凋亡。该项目基于一种范式转换假设，该假设认为糖尿病的潜在异常是棕榈酸盐在包括视网膜在内的外周非脂肪组织中代谢成生物活性神经酰胺的不适当。这一假设的一个推论是，胰岛素抵抗是新生神经酰胺合成增强的结果，导致胰岛素依赖性AKT信号的破坏。目前建议的总体假设是糖尿病神经酰胺代谢的改变导致膜微域（筏）内胰岛素受体功能障碍。我们的初步数据表明c16 -神经酰胺选择性地在糖尿病视网膜中积累，这可能是棕榈酸诱导的新生合成的结果。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那样。我们特别假设，脂质微域内神经酰胺的积累导致胰岛素受体信号传导减少，这是与信号元件或支架蛋白相互作用改变的结果。我们将使用复杂的生物化学，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。这些研究有可能确定神经酰胺积累作为一个靶标，可以治疗或分子操纵。

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.