Lin28B调控大鼠视网膜Müller细胞的重编程及其分子机制研究

项目名称： Lin28B调控大鼠视网膜Müller细胞的重编程及其分子机制研究

项目编号： No.81500736

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 陶醉

作者单位： 中国人民解放军第三军医大学

项目金额： 18万元

中文摘要： RP是一类以视网膜色素上皮变性为特点的遗传性致盲性疾病，目前尚无有效治疗方法。研究表明Müller细胞在低等脊椎动物中能作为内源性干细胞完全修复病变视网膜，而在哺乳动物中难以被激活发挥修复功能。我们前期发现在大鼠RP模型中，小分子蛋白Lin28B可通过抑制其下游分子let-7的表达从而促进Müller细胞再程序化，重新进入细胞周期，获得视网膜前体细胞特性，但其信号调节机制尚不清楚。鉴于Wnt信号在干细胞自我更新中的重要作用，且与Lin28有直接调控关系。据此我们推测，Lin28B调控Müller细胞重编程可能也受Wnt信号通路的调节。本课题拟采用RP大鼠模型，从离体和在体两方面深入探讨Lin28B/let-7是Müller细胞重编程的主要分子机制，证实Wnt信号通路通过与Lin28B启动子直接结合参与重编程调控过程。为利用内源性干细胞治疗RP提供新的策略和实验依据。

中文关键词： 视网膜色素变性；Müller细胞；重编程；Lin28B；Wnt信号通路

英文摘要： Retinitis pigmentosa (RP) is a hereditary blinding disease characterized by retinal pigment epithelial cells and photoreceptors’degeneration, necrosis and functional incapacitation. There is no effective treatment at present. Studies have shown that in lower vertebrates Müller cells act as endogenous stem cells to completely repair degenerative retina. While in mammals Müller cells can not be activated as endogenous stem cells to participate in retinal repair. We found that in rat RP models the small molecular protein Lin28B could promote Müller cells reprogramming, acquire progenitor characteristics and re-enter into the cell cycle through inhibiting the expression of its downstream molecules, let-7e and let-7i. But the signal regulating mechanism is unclear. In view of the important role of Wnt signaling in Müller cells activation, and the direct regulation relationship between Wnt and Lin28B in breast cancer stem cells，We speculate that regulation of Lin28B in Müller cells reprogramming may be affected by Wnt signal pathway. This project aims to deeply explore the regulation of Lin28B in Müller cells reprogramming during retinal repair in RP retina, and vertify the relationship between Wnt signaling pathway and Lin28B in this process. Our study will provide the new strategie and experimental basis for utilizing endogenous stem cells for the treatment of RP.

英文关键词： retinitis pigmentosa(RP);Müller cells;reprogramming;Lin28B;Wnt signal pathway