Crb2b通过招募DLIC1调节视锥细胞极性、纤毛形成及发育的机制研究

视网膜色素变性（RP）是一种遗传性致盲眼病，光感受器细胞进行性死亡是导致其视力丧失的主要原因，因而对光感受器细胞退变机制的研究非常重要。CRB1基因突变与RP相关，但其致病机制未明。斑马鱼Crb2b功能与人类CRB1功能相同，目前尚未有在斑马鱼模型中验证该基因功能的相关报道。课题组前期在成功构建crb2b转基因斑马鱼的基础上，发现Crb2b功能抑制后视网膜各个区域视锥细胞大量死亡，存活的少量视锥细胞也丧失了典型的马赛克结构；同时发现Crb2b与DLIC1在维持细胞粘附间具有紧密相关性。本项目拟在前期研究基础上，采用斑马鱼为动物模型，通过细胞分子生物学、组织病理学、电镜及ERG等实验技术，明确Crb2b顶端极性蛋白在视锥细胞发育中的作用，揭示其维持视锥细胞极性与粘附、中心体迁移、纤毛形成的机制，解析该类基因突变在引起RP发生发展中的作用机制，为探索新的治疗靶点和方案提供理论依据。

Retinitis pigmentosa (RP) is a hereditary blindness disease. The progressive death of photoreceptor cells is the main cause of vision loss. Therefore, it is very important to study the mechanism of photoreceptor cell degeneration. CRB1 gene mutation is associated with RP, but its pathogenesis is unknown. The function of Crb2b in zebrafish is the same as that of human CRB1. There are no reports to verify the function of Crb2b in zebrafish models. On the basis of the successful construction of crb2b transgenic zebrafish, we found that a large number of cone cells died and a small number of surviving cone cells lost their typical mosaic structure after the inhibition of Crb2b function. At the same time, we found that there was a close correlation between Crb2b and DLIC1 in maintaining cell adhesion. On the basis of previous studies, by using cell molecular biology, histopathology, electron microscopy and ERG techniques, this project is aimed to clarify the role of Crb2b in the development of zebrafish cone cells, to reveal the mechanism of Crb2b in maintaining cone cell polarity and adhesion, centrosome migration and cilia formation, and to analyze the mechanism of this gene mutation in the occurrence and development of RP. The results will provide theoretical basis to explore new therapeutic targets and schemes for RP.