促红细胞生成素通过调控小胶质细胞治疗糖网病作用机理研究

Diabetic retinopathy (DR) is one of the leading causes of legal blindness in the world. Microglia plays an important role in the pathogenesis of DR. In our series study, we found that the macular edema was significantly reduced and the hard exudates were obviously cleared in the patients with chronic and progressive diabetic macular edema, who underwent intravitreal injection of erythropoietin (EPO). This effect might be due to the regulation of EPO on retinal microglia. Thus, it is of importance to study the mechanism of intravitreal EPO regulating microglia and to find new targets in experimental diabetic retinopathy. In this project, we will study the regulations of intravitreal EPO on retinal microglia, e.g., activation, response, signal transduction pathways, and potential targets, etc. The obtaining results may facilitate to establish a library of targeted small molecules for future application. The significant contribution of this study is three-ford. First, we propose a new conceptual approach for DR treatment through regulation of retinal microglia; second, we will identify microglia-specific signal transduction pathways and key factors by which the altered functions of retinal microglia can be regulated. Third, after analysis of these molecular events in the regulation of microglia, the database of small-molecule drugs that target the specific functions of microglia may be established.

糖尿病视网膜病变（简称“糖网病”）是全球主要致盲眼病之一，小胶质细胞在糖网病的发病中起重要作用。本课题组前期临床研究发现，糖尿病视网膜黄斑水肿患者经眼内注射促红细胞生成素（EPO）治疗后，患者视网膜黄斑水肿显著消退、硬性渗出斑块显著缩小甚至消失，提示EPO可能通过调控视网膜小胶质细胞发挥了其对视网膜的保护作用。因此，阐明EPO调控小胶质细胞机理对拓宽EPO保护机理及发现新的治疗靶点具有重要意义。本研究以糖尿病大鼠为模型，研究眼内注射EPO对小胶质细胞的调控及机制，包括小胶质细胞的活化、效应、信号转导通路及潜在治疗靶点等。该研究具有如下意义：在治疗方面，从调控小胶质细胞入手，提出糖网病治疗的新理念、新思路；在机理方面，阐明糖网病状态下小胶质细胞特异的信号转导通路改变；同时，建立小胶质细胞靶标数据库，为筛选眼内小胶质细胞靶向药物提供参考。

糖尿病视网膜病变（简称“糖网病”）是全球主要致盲眼病之一，小胶质细胞在糖网病的发病中起重要作用。基于我们临床研究发现，糖尿病视网膜黄斑水肿患者经眼内注射促红细胞生成素（EPO）治疗后，患者视网膜黄斑水肿显著消退、硬性渗出斑块显著缩小甚至消失，提示EPO可能通过调控视网膜小胶质细胞发挥了其对视网膜的保护作用。因此，阐明EPO调控小胶质细胞机理对拓宽EPO保护机理及发现新的治疗靶点具有重要意义。本研究以糖尿病大鼠为模型，研究了眼内注射EPO对小胶质细胞的调控及机制，包括小胶质细胞的活化、效应、信号转导通路及潜在治疗靶点等。在研究中，我们发现糖网病中小胶质细胞激活、迁移能力和吞噬能力增强，炎症因子释放增加。激活的小胶质细胞可穿过基底膜吞噬或损伤内皮细胞，导致血-视网膜内屏障破坏，进而引起血管渗漏增强。而EPO可以抑制小胶质细胞激活，并通过激活Src/Akt/cofilin通路及抗炎等通路抑制小胶质细胞的吞噬能力，从而保护内皮细胞免受破坏，保护血-视网膜内屏障并减轻渗漏。此研究结果已整理成文，待投稿。本研究具有如下意义：在治疗方面，从调控小胶质细胞入手，提出糖网病治疗的新理念、新思路；在机理方面，阐明糖网病状态下小胶质细胞特异的信号转导通路改变。本研究为筛选眼内小胶质细胞靶向药物提供参考。.在本项目的资助下，已发表17篇科研论文，其中SCI论文16篇，中文综述1篇。以（共同）通讯作者发表7篇，其中SCI论文6篇、综述1篇；参与发表SCI论文10篇。文章发表在Eye、Invest Ophthalmol Vis Sci、Clin Exp Ophthalmol、Exp Eye Res等杂志上。