基于致病机制筛选治疗家族性渗出性玻璃体视网膜病变的化学小分子

Familial exudative vitreoretinopathy (FEVR) is a hereditary retinal peripheral vascular disorder. Mutations in four genes, including NDP, FZD4, LRP5 and TSPAN12, can cause this disease, and all of these four genes participate in the Wnt/Norrin pathway, but the specific mechanism of its signaling process is unclear. In addition, there is little option for the treatments of FEVR, so it is pressed for discovering effective small molecules specific to FEVR. Some cases of FEVR don't show any symptoms and never become a problem but for some others it can be a devastating disease even in a same family. Diet may be one of the factors leading to this difference; it indicates that there may be some small molecules from natural products can affect the function of FEVR pathogenic genes. Given this, we will establish a novel small molecule screening system based on previously identified mutations in FEVR related genes and the pathogenic mechanism of FEVR to discover small molecules from natural products library that can affect the function of FEVR pathogenic genes. On the one hand, the active small molecule can be used as a probe to further study the mechanism of Pathogenic mutations in FEVR. On the other hand, it can be used as lead compounds for FEVR therapy in the future.

家族性渗出性玻璃体视网膜病变(FEVR)是一种周边视网膜血管发育异常的遗传性疾病，已发现有四个基因（FZD4,NDP,LRP5和TSPAN12）发生突变会导致FEVR，这四个基因均与wnt/Norrin信号通路相关，但其信号过程中诸多调控机制仍不清楚；针对FEVR的治疗手段更是匮乏，亟需发现针对FEVR疾病的小分子药物。该病具有明显的临床异质性，即使在同一家系内也可以表现为无临床症状到致盲，饮食等因素可能是导致这种差异的因素之一，这提示了可能有来自天然产物的化学小分子能够影响FEVR致病基因功能。鉴于此，本项目将在前期已鉴定的FEVR致病突变的基础上，基于其致病机制建立细胞筛选模型，从化合物库中筛选能够影响FEVR致病基因功能的化学小分子，一方面以筛选得到的活性化学小分子为探针进一步深入研究FEVR致病突变分子机制；另一方面为开发针对FEVR疾病的特异药物提供可能的药物先导化合物。