原发性开角型青光眼(POAG)具有临床和遗传异质性，MYOC是重要的致病基因。我们前期研究发现了中国最大家系MYOC新的致病位点，携带突变的患者表现为较高眼压和严重的视神经损伤，但其发病机理仍不明确。MYOC可能通过蛋白错误折叠并异常蓄积和减弱小梁网细胞活性致病。小梁网可以形成myocilin-cryab复合体，可能是POAG新的致病靶点。本项目以分子伴侣cryab入手，以myocilin-cryab复合体功能异常可能导致小梁网房水流出受阻和视网膜神经节细胞凋亡导致POAG的假说开展研究。从细胞水平筛选MYOC突变库，寻找适合构建动物模型的MYOC突变体，建立MYOC突变型的细胞和青光眼小鼠动物模型；采用局部药物干预的方法，初步探索青光眼药物精准医疗的可行性。本项目的顺利开展，有望从分子伴侣致病、解除蛋白聚集、抑制细胞凋亡出发，探讨青光眼发病新的机制，为临床应用提供有意的参考依据。

Primary open-angle glaucoma (POAG) presents obvious clinical and genetic heterogeneity, and MYOC is an important pathogenic gene. In our previous study, we found a novel pathogenic locus of the largest pedigree in China, while the pathogenesis was still unclear. Previous studies have shown that MYOC may lead to glaucoma by misfolding accumulating the abnormal protein as well as weakening the activity of trabecular reticulum cells. Trabecular reticulum is a key channel of aqueous humor outflow, which can form myocilin-cryab complex and is a new pathogenic target of the obstructed outflow of aqueous humor from trabecular reticulum and apoptosis of retinal ganglion cells in POAG. Starting with molecular chaperones cryab, this project is based on the hypothesis that the abnormal function of myocilin-cryab complex leads to the POAG. The MYOC mutant library was screened from the cell level to search for mutants suitable for the construction of animal models. To preliminarily explore the feasibility of precision medicine for glaucoma by means of local drug intervention. The pathogenesis of glaucoma was studied based on the abnormal molecular chaperone, protein depolymerization and apoptosis inhibition, so as to provide a meaningful reference for clinical application.