青光眼是导致后天失明的第二大眼病，青光眼中视网膜神经节细胞（RGC）死亡是视觉功能丧失、致盲的主要病理原因。目前临床上治疗青光眼主要使用手术或药物手段降低眼内压，缺乏干预RGC细胞死亡进程的药物。研发神经保护药物的瓶颈之一是缺乏靶点及对RGC死亡分子机制的了解。有研究表明，钙离子超载是青光眼中RGC死亡的关键病变。我们发现，基因敲除小鼠tousled-like kinase 2(TLK2)可抑制青光眼模型中RGC细胞死亡。进一步研究发现，TLK介导的细胞死亡方式与已知的死亡方式不同。本研究计划旨在确定TLK参与青光眼中RGC死亡后，探索TLK介导细胞死亡分子机制，并在低氧低糖诱导钙超载引起RGC死亡模型中筛选针对TLK的小分子抑制剂，在小鼠急慢性青光眼模型中探寻TLK抑制剂的神经保护作用。

Glaucoma is the second leading cause of later life blindness. The death of retinal ganglion cells (RGC) in glaucoma is the main pathological cause of visual impairment and blindness. Currently, treatments of glaucoma mainly focus on reducing intraocular pressure by drugs or surgical means, and there are no available drugs to reduce the death of RGCs. One of the bottlenecks is the lack of drug targets and the limited knowledge on the mechanism of the death of RGC in glaucoma. Some studies suggest that calcium overload plays a key detrimental role during RGC death in glaucoma. We found that knocking out of TLK2 could inhibit the death of RGC in experimental glaucoma models. Further, the cell death mediated by TLK is different from known forms of cell death. This project aims at exploring the mechanisms of TLK-mediated cell death. We also try to screen the specific inhibitors that target TLK. At last, we would like to investigate the effects of these TLK inhibitors in acute and chronic glaucoma models.