Ndrg2调控Nrf2-ARE抗氧化通路在皮肤光老化中的作用和机制研究

皮肤光老化严重影响美观并诱发多种皮肤疾病，危害严重。氧化应激是光老化损伤核心机制，Nrf2-ARE是细胞内最重要的抗氧化通路。ndrg2是与衰老相关的应激反应基因；申请人前期发现ndrg2参与氧糖剥夺介导的氧化应激损伤。但ndrg2在皮肤光老化中的作用未见研究。申请人预实验发现：①UVB照射显著增加小鼠皮肤和HaCaT细胞NDRG2表达；②慢病毒下调ndrg2表达显著减少UVB照射后HaCaT细胞凋亡，减少ROS和MDA含量，增加Nrf2磷酸化水平和SOD活性；初步提示：ndrg2通过调控Nrf2-ARE抗氧化通路参与光老化氧化应激损伤，但确切作用和分子机制还不清楚。本课题拟利用表皮特异性ndrg2敲除小鼠和ndrg2上下调慢病毒，构建在体离体光老化模型，采用形态学、分子生物学、蛋白质组学等技术，阐明ndrg2在皮肤光老化氧化应激损伤中的作用及分子机制，为防治皮肤光老化提供新的分子靶点。

Skin photoaging seriously affects the appearance and also lead to many kinds of skin diseases, which is serious harmful to human beings. Oxidative stress is the core mechanism of photoaging damage, and Nrf2-ARE signal is the most important antioxidant pathway. Ndrg2 is a stress response gene related to aging. In previous study, the applicant found that ndrg2 was involved in oxidative stress injury induced by oxygen glucose deprivation. However, the role of ndrg2 in skin photoaging has not been studied. Our pre-experimental results found that: (1) UVB irradiation significantly increased the expression of NDRG2 in mouse skin and HaCaT cells; (2) down-regulation of ndrg2 by lentivirus significantly reduced the apoptosis of HaCaT cells, decreased the content of ROS and MDA, and increased the phosphorylation level of Nrf2 and SOD activity after UVB irradiation. These results indicated that ndrg2 may participate in oxidative stress injury of photoaging by regulating Nrf2-ARE antioxidant pathway, but the exact effect and molecular mechanism are still exclusive. By using the skin specific ndrg2 knockout mice and ndrg2 up- or down-regulation lentivirus, constructing photoaging model both in vivo and in vitro, and using morphology, proteomics and molecular biology technologies, this project aims to elucidate the role and molecular mechanisms of ndrg2 in oxidative stress injury of skin photoaging, which may provide a new molecular target for the prevention and treatment of skin photoaging.