基于Norrin/β-catenin信号调控的家族性渗出性玻璃体视网膜病变致病机制研究

家族性渗出性玻璃体视网膜病变（Familial exudative vitreoretinopathy, FEVR）是一种视网膜血管发育紊乱导致的眼科疾病，具有遗传和临床异质性，且对其治疗手段匮乏。以往研究表明，Norrin/β-catenin通路相关基因突变致该通路失活是导致FEVR的主要原因，但我们发现Norrin/β-catenin通路异常激活亦可导致FEVR，但具体致病机制有待阐明。本课题拟利用前期构建的两组Norrin/β-catenin通路异常激活和失活导致的FEVR小鼠模型，开展单细胞转录组、蛋白组分析，寻找受Norrin/β-catenin信号调控的下游关键基因和级联信号。随后利用免疫印迹、免疫组化以及AAV病毒介导的挽救实验进行验证，从而阐明这两类突变的致病分子机制，并揭示与FEVR临床异质性相关的信号调控过程。该课题有望为FEVR的诊治提供新的靶标，具有基础和临床意义。

Familial exudative vitreoretinopathy (FEVR) is an ophthalmic disease caused by disordered retinal vascular development. FEVR has genetic and clinical heterogeneity and lacks treatment methods for it. Previous studies have shown that Norrin/β-catenin signaling pathway-related gene mutations that reduce the activity of this pathway are considered to be the main cause of FEVR, while we found that mutations lead to hyperactivation of Norrin/ β-catenin pathway can also cause FEVR, but the specific pathogenic molecular mechanism remains to be elucidated. This project intends to use the two groups of FEVR mouse models that have been previously constructed due to abnormal hyperactivation and hypoactivation of the Norrin/β-catenin pathway, and carry out single-cell transcriptome and proteomic analysis to find the downstream genes and cascade signals. Then we will conduct immunoblot, immunohistochemistry, and AAV virus-mediated rescue experiments to verify the proposed pathway and finally elucidated the pathogenic mechanism of these two types of mutations, and reveal the signal regulation processes related to clinical heterogeneity of FEVR. This project is expected to provide new targets for the diagnosis and treatment of FEVR, which has basic and clinical significance.