线粒体Sirtuin酶在青光眼视神经变性的作用和分子机制

Glaucoma is an irreversible, blindness-causing illness characterized by progressive optic nerve and axonal degeneration. The mechanism for such degeneration, however, is unclear. Research has indicated that glial cell activation and RGC apoptosis may play a role in the process. The applicant research team has investigated optic nerve protection and regeneration in glaucoma extensively, and our previously studies show that activation of glial cells induces the production of pro-inflammatory factors and secondary RGC apoptosis. Animal models also demonstrate that NMDA receptor activation mediate RGC apoptosis in glaucoma. We recently conducted a comprehensive study of the expression characteristics of Sirtuins（Sirt 1-7）in retina, the first such study of its kind, and found that mitochondrial Sirts enzyme play a role in astrocytes. We also made the novel discovery that the pathological mechanisms of Sirt1 agonists and mTOR inhibitors in regulating the production of astrocyte activated inflammatory factors and in mediating the apoptosis of glaucoma RGCs. We hypothesized that the metabolic disturbance of mitochondrial Sirtuins enzyme is involved in RGC survival and glial/astrocytes activation. To research this hypothesis, we will further investigate the role of mitochondrial Sirtuins in retinal development, injury, degeneration and related regulatory conduction pathways at the cellular and animal levels. This study will further define the development mechanism of glaucoma from a novel perspective, and provide a new target for the prevention and treatment of glaucoma.

青光眼是进行性视神经和其轴突变性的不可逆致盲眼病，其机制不明，研究认为可能与胶质细胞活化和RGC凋亡有关。申请人长期从事青光眼视神经保护再生机制的研究，前期研究结果认为胶质细胞活化诱导促炎性因子产生与继发性RGC凋亡有关，动物模型也证明NMDA受体激活介导青光眼RGC凋亡。近期研究首次全面系统分析了Sirtuin酶（1-7）在视网膜的表达特点，发现线粒体Sirts酶在胶质细胞作用特点；我们也首次发现了Sirt1激动剂和mTOR抑制剂调控胶质细胞活化的炎性因子产生而介导青光眼神经细胞凋亡的病理机制。我们推测线粒体Sirtuin酶的代谢紊乱参与RGC和视神经乳头星型胶质细胞的能量代谢而介导青光眼损害。为证实这一假说，我们将从细胞和动物水平进一步观察线粒体Sirtuin酶在视网膜发育损伤变性过程中的作用和相关的调节传导通路。本课题将从一个全新的视角阐明青光眼发生机制，为青光眼防治提供新靶点。

青光眼是一类与年龄相关的衰老疾病，是严重影响人类视觉健康的致盲性眼病，其机制不明。目前研究认为可能与胶质细胞活化继发的视网膜神经节细胞（RGC）凋亡有关。本项目的目的在于探索线粒体功能紊乱与青光眼神经变性保护的相关性机制。在本项目的支持下我们主要聚焦在线粒体Sirt4蛋白酶与青光眼视网膜损伤的机制的研究。首先我们分析了SIRT4在视网膜的定位，明确了它与muller细胞的密切关系以及在视网膜发育及损伤过程中的关键作用，我们也探讨了靶向代谢功能的SIRT1激动剂白藜芦醇（RSE）是通过调控Ampk/Sirt1/Pgc1α和 Akt/mTOR 信号通路保护视网膜线粒体功能而达到抗视网膜衰老变性的作用，我们也明确了RES可以调控Opa1蛋白和抑制AMPK/mTOR信号通路以及r-MC的自噬而保护视网膜损伤。我们的研究进一步阐明了SIRT4在抗青光眼神经变性的作用，本课题的成果有利于我们以一个全新的视角理解青光眼发生机制，为青光眼防治提供新靶点。