Gαi-Akt-mTOR信号轴在视网膜色素上皮细胞增殖和迁移中的作用及机制研究

Age-related macular degeneration(AMD) and proliferative vitreoretinopathy (PVR) are common causes of severe visual loss and blindness. Better understanding of the pathological mechanism of AMD and PVR is thus vital for better management of the disease. In the process of AMD and PVR, retinal pigment epithelial (RPE) cells are affected by a variety of cytokines in vitreous, resulting in RPE cell activation, proliferation and migration, which is critical for AMD and PVR initiation and development. Here we propose to study the cellular mechanisms and signaling pathways that are involved in this process. Our preliminary in vitro study discovered a Gαi-Akt-mTOR signaling axis that is important for TNF-α (Tumor necrosis factor-α) and NGF (Nerve growth factor) induced RPE cell migration and proliferation. Using both in vitro and in vivo methods, we here propose to further investigate pathological mechanisms, in particular， the signaling pathways that cause RPE cell migration and proliferation by focusing the Gαi-Akt-mTOR signaling axis. We aim to indentify novel molecular targets and propose possible new strategies against AMD, PVR and other proliferative retinopathy diseases.

视网膜色素上皮(Retinal pigment epithelium， RPE)细胞受多种细胞因子诱导产生增殖及迁移，在常见致盲性眼病如年龄相关性黄斑变性（AMD）和增生性玻璃体视网膜病变（PVR）的发生发展中起重要作用，其分子机制研究是近年来的研究热点。本项目组前期体外研究证实Akt-mTOR(哺乳动物雷帕霉素靶蛋白)通路参与体外TNF-α (肿瘤坏死因子-α)及NGF(神经生长因子)等细胞因子诱导的RPE细胞的增殖和迁移，并首次发现Gαi1和Gαi3蛋白作为表皮生长因子(EGFR)信号通路中新的关键支架蛋白介导下游信号Akt/mTOR活化。本项目旨在通过体外实验明确Gαi-Akt-mTOR信号轴介导RPE细胞增殖和迁移的分子机制，并通过在体研究明确Gαi-Akt-mTOR信号轴与AMD和PVR的相关性，从而为AMD及PVR的预防和治疗提供新的思路及新的药物治疗靶点。

视网膜色素上皮细胞（RPE细胞）的增殖及迁移对增生性玻璃体视网膜病变（PVR）的发生发展中起重要作用。我们前期发现Akt-mTOR(哺乳动物雷帕霉素靶蛋白)通路调控RPE细胞增殖和迁移，Gαi1 和Gαi3 蛋白介导下游信号Akt/mTOR活化。本项目明确了Gαi-Akt-mTOR 信号轴介导RPE细胞增殖和迁移的作用，确定了Gαi-Akt-mTOR信号轴与PVR的相关性，从而为PVR的预防和治疗提供新的思路及新的药物治疗靶点。