EPO/EPOR对早产儿视网膜病变模型鼠视网膜胶质细胞功能的影响及相关机制研究

Retinopathy of prematurity is the major ocular disorder of the neonate and the dominant cause of severe impairment in childhood. The further study on the mechanism of ROP not only helps to elucidate the pathogenesis of ROP, but also provides potential targets for early treatment. Erythropoietin exerts antioxidative, antiapoptotic and angiogenetic effects. Our preliminary study showed that the expression of EPO/EPOR dropped at both gene and protein level in the early stage of ROP. It hints that EPO and EPOR may play important roles on the pathogenesis of ROP. Retinal astrocytes have been proposed to playing important role in regulating retinal vascular development by secreting cytokines. This research will culture both retinal astrocytes and endothelial cells under hyperoxia and study the influence of endogenous increased or decreased EPO expression to the retinal astrocytes by lentivirus mediated overexpression and knockdown EPO gene in cellular and animal level. This research will also study the signaling pathway of EPO/EPOR in order to elucidate the pathogenesis of ROP and provide a hopeful medicine to prevent and treat ROP.

早产儿视网膜病变（ROP）是目前世界范围内新生儿致盲的主要原因之一，对其发生机制的深入探讨不仅有助于阐明ROP的发病机制，而且为早期治疗提供潜在靶点。促红细胞生成素（EPO）是具有抗氧化损伤、抗细胞凋亡及促血管生成作用的多功能细胞因子。我们前期研究结果显示在早产儿视网膜病变早期EPO及其受体在基因和蛋白水平表达下降，提示EPO及其受体在早产儿视网膜病变发生发展中扮演一定的角色。EPO的效应器视网膜星形胶质细胞可通过分泌细胞因子对视网膜血管发育起重要的调节作用。本课题拟体外培养视网膜星形胶质细胞和视网膜血管内皮细胞，以高氧模拟早产儿视网膜病变的早期病理环境，以慢病毒介导EPO基因过表达及基因敲减为干预手段，在细胞和动物水平验证内源性增加或抑制EPO表达对视网膜星形胶质细胞生物学特性的影响，并研究EPO-EPOR信号通路，初步阐明早产儿视网膜病变发病机制，为早期治疗早产儿视网膜病变提供新思路。

早产儿视网膜病变(ROP)是目前世界范围内新生儿致盲的主要原因之一，对其发生机制 的深入探讨不仅有助于阐明ROP的发病机制，而且为早期治疗提供潜在靶点。促红细胞生成素(EPO)是具有抗氧化损伤、抗细胞凋亡及促血管生成作用的多功能细胞因子。本课题研究发现EPO的效应器视网膜星形胶质细胞可通过分泌细胞因子对视网膜血管发育起重要的调节作用。本课题通过体外培养视网膜星形胶质细胞和视网膜血管内皮细胞，以高氧模拟早产儿视网膜病变的早期病理环境，以慢病毒介导EPO基因过表达为干预手段，在细胞和动物水平证实内源性增加EPO表达影响应激状态下的视网膜星形胶质细胞生物学特性，可有效减少视网膜血管闭塞的发生，从而降低随之而来的视网膜新生血管的发生率。同时本课题对相关信号通路进行了研究，通过real-time PCR和Western-blot在转录水平和蛋白水平均发现EPO可能是通过GDNF/ERK信号通路进行调控的，初步阐明早产儿视网膜病变发病机制，并为早期治疗早产儿视网膜病变提供新思路。