青光眼视神经病变是以视网膜神经节细胞（RGC)进行性丢失为病理基础的首位不可逆致盲眼病。目前临床上的防治措施只能一定程度上缓解病情发展却无法遏制RGC进行性死亡。迫切需要深入研究青光眼RGC死亡机制，探寻新的防治靶点。线粒体DNA（mtDNA）对细胞的存活和死亡起着至关重要的调控作用。申请人在前期工作中发现大鼠慢性高眼压RGC发生mtDNA突变，且在眼压恢复正常后仍累积性增加，提示其在RGC进行性死亡中可能扮演重要角色。本课题拟在此基础上，深入研究大鼠慢性高眼压RGC累积性mtDNA突变的分子特点和发生机制、mtDNA突变导致RGC死亡的关键环节，探讨mtDNA突变加重RGC对眼压和谷氨酸浓度升高的易损性、以及减少mtDNA突变对高眼压RGC的保护作用。旨在阐明累积性mtDNA突变在青光眼RGC死亡，尤其是眼压恢复正常后的进行性死亡中的关键作用和机制。为探寻有效的临床治疗靶点提供实验依据。

Glaucomatous neuropathy is the first blindness disease characterized by progressive loss of retinal ganglion cells (RGC ). The therapeutic strategy now in clinic only delayed the RGC death, other than stopped the progressive death. It is necessary to study the mechanism of RGCs death in glaucoma and seek a novel therapeutic target. Mitochondrial DNA (mtDNA) is critical to cell survival and death. We found that mtDNA mutations occured in the RGCs of chronic ocular hypertension rat and cumulative increased even after high pressure return to normal level, suggesting the important role of mtDNA in the RGCs progressive death. Based on these results, in this project we study the molecular characterization and mechanisms of cumulative mtDNA mutations, the critical points of mtDNA mutations resulting in RGC death, the susceptibility to secondary insult such as high ocular pressure and increasing glutamate after RGC contained more mtDNA mutations, and the neuroprotective effect of decreased mtDNA mutations on RGC in chronic ocular hypertension rat. The goal of this project is to demonstrate the vital role of cumulative mtDNA mutations in the progressive RGC death, especially when high pressure return to normal. The project is beneficial to search more effective therapeutic target in clinic.