视网膜变性是遗传性视觉损害和失明的最主要的原因之一，CERKL是2004年克隆的重要RP/CRD致病基因，但该基因功能及其突变引起视网膜变性的分子机制尚不清楚，在小鼠中敲除CERKL未能检测到RP/CRD的表型。前期工作中，我们应用TALEN技术成功构建了CERKL敲除的斑马鱼模型，观察纯合缺失的斑马鱼发现其产生类似视网膜变性的临床症状；检测突变体视网膜的cGMP水平发现其浓度显著升高，提示CERKL缺陷可能通过上调cGMP而引起视网膜变性。本项目将前期工作基础上,通过对不同发育时期的斑马鱼进行观察和分析，研究CERKL突变导致RP/CRD的病理过程;分析CERKL调控cGMP在视觉形成过程中的作用机制,揭示CERKL突变导致感光细胞死亡的信号通路。本研究不仅将明确CERKL在视网膜中的生理功能，揭示该基因突变引起视网膜变性发病的病理机制，并将为视网膜变性的有效预防和治疗打下良好基础。

Retina degeneration is one of the major causes that leads to hereditary visual impairment and blindness. There is no effective treatment for the disease so far. CERKL is an important RP/CRD pathogenic gene, although both its physiological and pathological roles remain unknown. No RP/CRD phenotype has been detected in CERKL knockout mice. In our previous studies, a CERKL knockout zebrafish model has been generated by using TALEN technique. Histology observation demonstrated a typical RP/CRD phenotype in the CERKL-null fish, accompanied by a significant rise of cGMP level in the retina. This proposal is aimed to investigate the pathological processes, especially the specific pathways leading to cGMP up-regulation and photoreceptor death, in retina of CERKL knockout zebrafish. This study will not only uncover the important roles of CERKL in retina physiology, but also provide evidences and support in developing effective strategy for RP/CRD prevention and treatment.