GPX1基因原发性开角型青光眼致病机制研究

Primary open angle glaucoma (POAG) is the most common form of glaucoma and one of the leading causes of irreversible blindness and visual damage. Currently， there are no effective methods for prevention or treatment of POAG. Genetic factors have been shown to play an important role in the pathogenesis of POAG. We have performed Exome Sequencing with 396 POAG cases and 400 controls in a Han Chinese population and found that the GPX1 gene was a causal gene for POAG. Several studies showed that the antioxidant enzyme activity of aqueous humor in POAG patients was lower than that of normal people, but the mechanism of GPX1 in POAG remains unknown. According to previous reports and our preliminary results, we hypothesized that the GPX1 gene may participate in the regulation of POAG by its antioxidant function. We will carry out functional study on the GPX1 gene by cell biology in signal pathway and Knockout Mouse model to disclose the mechanism of POAG. This study will clarify how GPX1 is involved in the development of POAG and provide clues for the prevention and treatment of POAG.

原发性开角型青光眼（POAG）是最常见的一类青光眼，也是不可逆的致盲和视力损伤眼病，尚无有效防治手段。遗传因素在POAG发病中起着重要作用，通过对POAG疾病基因的研究，可阐明其发病机制。前期研究中，我们通过396例汉族人POAG和400例对照外显子测序并扩大样本验证，鉴定了一个新的POAG致病基因GPX1。以往有研究发现POAG患者房水的抗氧化酶活性低于正常人，但其调控模式和作用机制并不清楚。结合文献报道和前期的实验结果，我们提出了“GPX1基因可能通过它的抗氧化应激功能参与调控POAG的发生发展”的假说，拟通过体外实验在细胞水平确定GPX1相互作用蛋白，应用表达谱芯片鉴定随GPX1变化而表达变化的基因，揭示其在信号通路中的作用；通过体内实验，用基因敲除小鼠模型研究GPX1基因在POAG发生过程中的作用，来探索GPX1的POAG 致病机制，为POAG有效防治提供理论依据和可能的干预靶点。

原发性开角型青光眼（POAG）是最常见的一类青光眼，也是不可逆的致盲和视力损伤眼病，尚无有效的防治手段。遗传因素在POAG发病中起着重要作用，已知基因的突变只能解释5-6%的POAG。通过对POAG疾病基因的研究，可阐明其发病机制。本项目收集了大量的POAG和对照样本（原发性开角型青光眼病例已收集5000例，年龄及性别匹配的正常对照10000余例）。对396例POAG病例和400例相应的对照进行了外显子测序分析，经过初步的筛选和验证，已经确定几个新的候选基因，并进行了功能研究和易感基因的关联分析等，以找到更多新的POAG致病基因和连锁位点，并对致病基因进行深入的功能研究，探索POAG的致病机制。这些研究成果进一步为阐明POAG致病机制提供了线索，在临床上为POAG的分子诊断、早期干预和基因治疗提供重要信息，可作为理论基础、数据基础为系统研究POAG人群的患病机制指明方向，为POAG有效防治提供理论依据和可能的干预靶点。