Nmnat1在糖尿病视网膜病变中的视神经保护作用及其机制研究

糖尿病性视网膜病变（Diabetic retinopathy，DR）是世界性主要致盲眼病之一，除微血管改变外，视网膜神经退行性变是DR的另一重要病理特征。近年来的研究显示，视网膜神经改变甚或早于微血管改变的发生，其机制尚不完全清楚。我们前期研究发现，相比于野生型小鼠，WldS突变小鼠可以延缓糖尿病引起的神经胞体损伤和轴突变性；WldS突变小鼠具有较高的NAD+/NADH 比率和Nmnat1表达水平。作为NAD合成关键酶的Nmnat1被认为是WldS蛋白活性的重要区域，是视神经退行性疾病发生的重要调控蛋白。本项目拟构建离体、在体糖尿病模型，分析多个压力和时间点下Nmnat1的表达规律，通过药物和分子手段干预Nmnat1活性，探讨Nmnat1对糖尿病性视神经病变的调控作用，揭示其对糖尿病性视神经损伤的保护作用分子机制，以期为临床防治糖尿病视网膜病变提供新策略。

Diabetic retinopathy (DR) is one of the most common eye diseases causing blind. It is characterized by progressive optic nerve degeneration except vascular abnormalities. Recent studies have found that the pathologic changes of retinal nerve precede that of microvessel, but the mechanism is not fully understood. Our previous study has revealed that diabetes-related injury of retinal ganglion cell axons and soma is significantly delayed in WldS mutant mice compared with the wild type mice. Moreover, the NAD+/NADH ratio and Nmnat1 expression is significantly higher than that in wild type mice. Nmnat1, a key enzyme in NAD biosynthesis, is a crucial component for WldS protein, which functions as an important regulator in the development of many neurodegenerative diseases. Here, we will detect Nmnat1 expression pattern in glucose-induced cell apoptosis model and diabetic mouse model at different time points, clarify the role of Nmnat1 in diabetic neuropathy through in vitro or in vivo intervention of Nmnat1 expression, and reveal the potential molecular basis of Nmnat1-mediated diabetic neuropathy. This study would provide a new strategy for clinical prevention and treatment of diabetic retinopathy.