OPTN基因是原发性开角型青光眼（POAG）相关致病基因，OPTN与miR-9具有极高相关性，申请者前期研究证实OPTN(E50K)突变中miR-9参与p-CREB-REST通路调控BDNF表达致视网膜神经节细胞（RGCs）凋亡，但OPTN（E50K）突变致miR-9水平下调机制不清。考虑到OPTN（E50K）突变可干扰选择性自噬而影响TARDBP的正常降解、TARDBP蛋白又可调节Drosha和Dicer酶活性改变miR-9表达，本研究拟利用申请者已建立的体内外OPTN（E50K）突变转基因模型，过表达或抑制TARDBP，观察泛素化TARDBP聚合体的自噬降解、TARDBP蛋白与Drosha和Dicer酶的结合情况对miR-9表达和RGCs凋亡的影响，阐明OPTN基因突变对miR-9的调节机制和POAG发病的分子机制，为其将来临床更早期诊断和治疗提供新的分子标志和治疗靶点。

OPTN is known as a POAG related gene, and it is highly associated with miR-9. In our recent study, we demonstrated that miR-9 was involved in p-CREB-REST pathway regulating the expression of BDNF in OPTN(E50K) mutation induced RGCs apoptosis. However, the mechanism of the decreased miR-9 in OPTN(E50K) mutation is still unclear. Given that OPTN(E50K) mutation could impaire the selective autophagic degradation of TARDBP, and the function of TARDBP is regulating expression of miR-9 via modulating the activity of Drosha and Dicer complexes. We plan to research whether the overexpression or inhibition of TARDBP could alter the degradation of ubiquitinated aggregates of TARDBP, and to demonstrate the interaction between TARDBP and Drosha/Dicer that regulates miR-9 expression and RGCs apoptosis, which could elucidate the mechanism of OPTN gene altering miRNA in POAG and provide a diagnostic molecular marker and a novel therapy to glaucoma.