糖尿病视网膜病变(DR)涉及视网膜神经元与微血管双重病变，其本质是视网膜神经血管单元(NVU)的损伤，但目前旨在同时改善神经元与微血管功能的研究非常缺乏。Progranulin是一种具有免疫调节与神经保护作用的多功能生长因子。申请者前期发现：该蛋白存在于视网膜，其表达在糖尿病小鼠视网膜中显著降低；添加该蛋白可显著减轻缺氧条件导致的小鼠光感受器损伤与视网膜血管白细胞粘滞度，该保护作用与TLR4-NOX4信号通路相关。据此我们假设Progranulin能同时改善DR的神经元与微血管病变。本项目将采用动物和细胞实验，应用视网膜电图与屏障渗漏分析等方法，拟：1）研究Progranulin在DR条件下对神经元与微血管病变的保护作用；2）阐明TLR4-NOX4信号通路在上述保护作用中的机制。本申请研究单一物质对DR中神经元与微血管病变的双重保护作用，有望为DR的NVU病变提供治疗新途径和新思路。

Neuron degeneration and microangiopathy are both involved in diabetic retinopathy (DR) . DR is a retinal neurovascular unit (NVU) injury essentially. Currently, there are less researches on the overall treatment of NVU aiming to improve neuron and micrangium function. Progranulin is a multifunctional growth factor. It has the effect of immunomodulatory and neuron protection. The preliminary work found that Progranulin is expressed in the mice retina and downregulated in diabetic model. We also found that exogenous Progranulin could alleviate photoreceptors injury and retinal vascular adherent leukocytes under the hypoxic conditions. This protection effect is related with TLR4-NOX4 signaling pathway. Based on the preliminary experiment and research background, we propose the hypothesis that Progranulin could inhibit the retinal neurons and microvascular lesion through regulating the retinal TLR4-NOX4 signaling pathway under the diabetic conditions so as to protect the retinal NVU from high glucose damage. We will use animal and cell experiments by the means of electroretinogram and blood-retina barrier breakdown assays et al. We aim to investigate the protective role of Progranulin in DR and illustrate the mechanism of TLR4-NOX4 signaling pathway in the protection effect. Our work focused on the dual protection effect of neuron degeneration and microangiopathy by a single substance and would provide a new approach for the treatments of diabetic NVU injury.