组蛋白去甲基化酶Jmjd3调控小胶质细胞炎症因子表达及其参与RGCs损伤的机制

Glaucoma is an ocular disorder characterized by the progressive degeneration of the retinal ganglion cells (RGCs). Studies have shown that correlation exist between the inflammation and glaucoma. The activation of microglia that mediated the inflammation might be involved in the apoptosis of RGCs. However, the regulatory mechanisms of the apoptosis remain to be elucidated. Our previous work found that Jmjd3-mediated microglia increase the expression of the inflammatory cytokine induced by N-methyl-D-aspartate (NMDA). GSK J4, the inhibitor of Jmjd3, significantly inhibited the expression of these inflammatory cytokines. We speculated that Jmjd3 may participate in the regulation of the retinal microglia’s release of inflammatory factors and may be closely related to the RGCs damage found in glaucoma. In this project, we will target the Jmjd3 and investigate its effects on the regulation of microglia activation, relevent inflamatory cytokine expression, damage to RGCs, and the p38 MARK signaling pathway activation through the intervening Jmjd3 gene in both the NMDA-induced glaucoma model (in vivo) and the NMDA-induced cell model (in vitro). This study sought to explain the role of Jmjd3 in microglia’s mediating effect on the expression of inflammatory cytokine, to explain the control of the RGCs’ apoptosis, and to confirm Jmjd3 as a new drug therapy target for glaucoma treatments.

青光眼的主要病理特征为视网膜神经节细胞(RGCs)凋亡，研究认为青光眼与炎症存在相关性，小胶质细胞激活介导的炎症可能参与RGCs凋亡。然而它的调控机制有待阐明。我们前期研究发现兴奋性神经递质N-甲基-D-天门冬氨酸（NMDA）通过上调Jmjd3增加小胶质细胞炎症因子表达；Jmjd3的抑制剂GSK J4抑制NMDA诱导炎症发生。因此推测：Jmjd3可能是调控小胶质细胞炎症因子表达及青光眼RGCs损伤的关键基因。本研究以Jmjd3为靶点，以NMDA诱导的青光眼动物模型和NMDA诱导的小胶质细胞激活为研究对象，通过体内外干预Jmjd3的表达，研究Jmjd3调控小胶质细胞激活，相关炎症因子的表达，对RGCs损伤以及对p38 MARK信号通路激活的影响。本研究旨在探讨Jmjd3调控小胶质细胞炎症因子表达及其参与RGCs损伤的作用，以确定Jmjd3是否为青光眼治疗新靶点。

青光眼的主要病理特征为视网膜神经节细胞(retinal ganglion cells，RGCs)凋亡，研究认为青光眼与炎症存在相关性，小胶质细胞激活介导的炎症可能参与RGCs凋亡。视网膜神经节细胞（retinal ganglion cells，RGCs）的进行性凋亡是青光眼的病理基础。因此，深入研究如何减轻青光眼患者RGCs的损伤，探索其损伤的病理机制并寻找有效治疗的新靶点，对降低青光眼患者失明的风险和提高患者的生活质量有着重要的临床和现实意义。青光眼中高眼压或缺血或兴奋性神经递质等诱导microglia激活并分泌炎症因子等增加，进而引起RGCs凋亡。这是青光眼RGCs受损的途径之一。组蛋白通过乙酰化和甲基化在表观遗传调控中发挥重要作用，尤其蛋白可逆甲基化修饰炎症调控中起到重要作用。组蛋白去甲基化酶Jmjd3可能参与调控Microglia的激活及炎症因子的表达。本研究从体外和体内两条途径来研究Jmjd3调控microglia炎症因子表达及其参与RGCs损伤的机制：1）体内外采用基因转染，siRNA及抑制剂，双向调节Jmjd3的表达，观察microglia炎症因子的表达变化，明确Jmjd3的调控作用；2）观察Jmjd3是否通过调控炎症因子表达参与RGCs的损伤；3）探讨Jmjd3调控microglia炎症因子表达及其参与RGCs损伤的分子作用机制。研究结果发现青光眼细胞模型中小胶质细胞可激活，炎症因子表达随之上调。炎症因子表达上调的同时Jmjd3表达亦明显上调。当上调的Jmjd3被抑制后，小胶质细胞中炎症因子表达明显下调。与之对应的是：Jmjd3表达亦明显下调。小胶质细胞激活后，RGCs明显受损。小胶质细胞激活，抑制Jmjd3表达后，RGCs受损明显减轻。研究的意义在于探讨Jmjd3调控小胶质细胞炎症因子表达及其参与RGCs损伤的作用，确定了Jmjd3是否为青光眼治疗新靶点。