感光细胞是人类重要的感觉神经元，却在多种常见的视网膜退行性病变中被损伤导致失明。某些物种如斑马鱼有强大的视网膜自我修复能力，因为MG细胞具有内源性干细胞的功能，可在组织损伤后去分化，分裂和再分化成感光细胞。然而哺乳动物的视网膜却缺乏再生能力，关键的障碍之一是成熟MG细胞不能有效进入细胞周期而分裂。我们的预实验结果显示，细胞周期调控蛋白p27Kip1在阻止MG细胞周期进入中可能起到决定性作用。我们发现使用腺相关病毒特异性地降低p27Kip1水平可有效促使MG细胞再次分裂。在此，我们将对p27Kip1在MG细胞受调控的分子机制展开研究， 并且在正常和损伤的视网膜中对p27Kip1进行功能丧失研究，确定抑制p27Kip1对于MG细胞再生的推动作用。本课题将为细胞周期抑制是否是视网膜再生的主要障碍这个问题提供答案，剖析神经组织再生受到抑制的分子机制，为促进组织自我修复的再生疗法指出新方向。

Photoreceptors are important sensory neurons of human being, but they are damaged and irreversibly lost in many retinal degenerative diseases, leading to blindness. Lower vertebrate species such as zebrafish have powerful retinal self-repair capability owing to Müller glia (MG) cells, which possess dormant resident stem cell property. Upon retinal damage, MG can partially de-differentiate, divide, and differentiate to replace the lost photoreceptors. However, this regenerative capacity of MG cells is lost in mammals. One of the key features of the limited regenerative capability is that MG cells can not re-enter cell cycle after injury. Our preliminary data show that cyclin-dependent kinase inhibitor p27Kip1 may play an important role in inhibiting MG cell cycle re-entry and suppressing regeneration. We use adeno-associated virus (AAV) to knock down p27Kip1 in MG cells specifically and find that it can promote MG proliferation in the explant model of retinal degeneration. In this study, we will investigate the molecular mechanism underlying p27Kip1 up-regulation in MG cells. To further determine the role of p27Kip1 in suppressing regeneration, we will carry out a loss-of-function study in both normal and degenerating retinas by AAV-mediated p27Kip1 knock-down in a MG-specific manner. Our study will answer the question whether cell cycle blockage is the major hurdle of MG-mediated regeneration. The long-term goal of our study is to shed light on the molecular mechanisms underlying the lack of regeneration in mammalian neuronal tissues and to point out new directions for regenerative medicine to treat retinal degenerative diseases.