年龄相关性黄斑变性（AMD）是老年患者致盲的重要原因。氧化应激所致视网膜色素上皮（RPE）细胞变性和凋亡在AMD中起重要作用。我们及合作者以往研究发现，氧化应激可诱导乙酰胆碱酯酶（AChE）表达，且AChE具有DNase活性，从而导致RPE细胞凋亡，但有关具体信号调控机制尚不清楚。本课题前期实验发现：过氧化氢处理ARPE-19细胞能激活NF-κB通路和诱导AChE表达；NF-κB抑制剂和ROS清除剂均能抑制过氧化氢所致NF-κB激活和AChE表达；敲低AChE能减轻过氧化氢诱导的细胞凋亡。基于文献报道和前期实验结果，我们推测：氧化应激可能经NF-κB通路上调AChE表达，AChE入核后通过其DNase活性介导染色体降解和细胞凋亡。为验证上述假说，将通过分子细胞和动物实验深入探讨氧化应激时NF-κB对AChE表达调控及诱导RPE细胞凋亡的机制。故本课题将为今后AMD防治提供可能的药物新靶点。

Age related macular degeneration (AMD) is the main cause of blindness in aged patients. The dysfunction of retinal pigment epithelium (RPE) and RPE cell apoptosis under oxidative stress play an important role in the pathogenesis of AMD. In previous studies, we and collaborators found expression of AChE was up-regulated under oxidative stress, and AChE exerted the function as DNase, which induces the apoptosis of RPE cells. However, the signaling mechanism of oxidative stress in AMD pathogenesis is still poorly defined. In the preliminary experiments, we found that H2O2 treatment activated NF-κB pathway and up-regulated expression of AChE in ARPE-19 cells. Pretreatment with NAC or BAY efficiently attenuated H2O2-induced activation of NF-κB and AChE expression. Importantly, knockdown of AChE by siRNA effectively alleviated H2O2-induced apoptosis of ARPE-19 cells. Based on our preliminary studies and the previous reports, we hypothesize that oxidative stress might up-regulated expression of AChE via NF-κB signaling pathway. AChE subsequently translocates to nuclear and mediated cleavage of chromosomal DNA via its DNase activity, which lead to RPE cell apoptosis. To prove our hypothesis, we will further investigate the underlying mechanism how NF-κB regulates the transcription and expression of AChE, and the mechanism of AChE mediating apoptosis in RPE cells in vitro and in vivo. Therefore, this study will provide a potential therapeutic target for AMD in the future.