青光眼是全球第二大致盲原因，开角型青光眼（POAG）是其主要类型之一。POAG以视网膜神经节细胞（RGC）凋亡为特征，与遗传因素紧密相关，但目前鉴定的POAG基因仅可解释约 5%的POAG发病。我们通过398例POAG和1374例对照样本的高深度全外显子组测序，挖掘到VAV2基因的稀有变异在POAG样本中显著富集；同时，我们通过大样本亚洲人群的POAG meta分析，发现VAV2基因内含子的SNP位点rs7852459与POAG显著相关；而文献报道Vav2-/-小鼠眼压升高，提示VAV2可能是POAG的疾病基因。为此，本课题在前期研究的基础上，开展VAV2基因与POAG的疾病机制研究，从突变/变异对功能的影响、RGC功能及信号通路维持、小鼠模型的表型等多方面开展研究，发现VAV2基因异常导致POAG的分子机制，为理解VAV2基因在调控RGC稳态中的关键作用和POAG的干预治疗提供依据。

Glaucoma is the secondary leading cause of blindness worldwide. Open-angle glaucoma (POAG) is one of its main types. POAG is characterized by apoptosis of retinal ganglion cells (RGC) and is closely related to genetic factors. However, only about 5% of the pathogenesis of POAG can be explained by the identified POAG genes. We performed 398 POAG and 1374 control samples‘’ whole exome sequencing, and found that the rare variants in VAV2 genes were significantly enriched in POAG samples. Meanwhile, we found that the SNP locus rs7852459 in the intron of VAV2 gene was significantly associated with POAG in the results of meta-analysis of POAG in Asians. The literature reported that intraocular pressure of Vav2-/- mice was increased. All these clues suggested that VAV2 might be a disease gene of POAG. Therefore, on the basis of previous studies, this proposal mean to explore the molecular mechanisms between VAV2 and POAG. We will study the effects of mutation/variation on the function of VAV2, the role of VAV2 in maintenance of RGC function, its signaling pathway, as well as the detailed phenotypes of Vav2-/- and hVAV2 knockin mice models. The results obtained from this study would provide proofs not only for understanding the key role of VAV2 gene in regulating RGC homeostasis but also for intervention therapy of POAG in the future.