The Role of Ceramide in Diabetic Retinopathy

描述(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导致视网膜神经元凋亡。该项目基于一个范式转换假设，该假设表明糖尿病的潜在异常是棕榈酸酯在外围非脂肪组织(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，胰岛素抵抗是从头合成神经酰胺增强的结果，导致胰岛素依赖的AKT信号中断。本研究的总体假设是糖尿病患者神经酰胺代谢改变导致膜微域(RAFT)内胰岛素受体功能障碍。我们的初步数据表明，C16-神经酰胺选择性地积聚在糖尿病视网膜中，这可能是棕榈酸诱导从头合成的结果。此外，外源性神经酰胺模拟糖尿病引起的胰岛素抵抗，表现为AKT活性和细胞存活率下降。我们特别假设，由于与信号元件或支架蛋白相互作用的改变，脂质微域中神经酰胺的积累导致胰岛素受体信号减弱。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。这些研究有可能将神经酰胺的积累确定为一个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.