从lncRNA H19介导炎症和凋亡探索青光眼神经损伤机制和治疗

In glaucomatous neuropathy, the irreversible death of retinal ganglion cells figures prominently, while the targeted therapeutic strategy remains scarce. The latest investigation revealed that long noncoding RNA (lncRNA) has a vital role in physiology and pathology. However, the effects and molecular mechanism in glaucoma need further illustration. Our study, published in PNAS in 2014, showed that the “caspase-8/NLRP3 inflammasome” signaling pathway facilitates inflammation and cell apoptosis through the activation of microglia. Recently, preliminary experiments found that silencing lncRNA H19 in acute glaucomatous model can upregulate microRNA-21 and downregulate PDCD4, caspase-8, NLRP3, thus inhibited cell death. In this study, we will clarify the molecular mechanism and role of inflammation and apoptosis induced by “lncRNA H19/microRNA-21/PDCD4/caspase-8” pathway in glaucomatous neuropathy via targeted regulations like medication and gene engineering in mouse acute and chronic glaucomatous models, aiming to evaluate the application prospect of targeted therapy and provide novel therapeutic targets and theoretical foundation for glaucoma.

视网膜神经节细胞不可逆性死亡是青光眼神经损伤的重要环节，目前尚缺乏有效靶向治疗手段。最新研究表明，长链非编码RNA（lncRNA）在多种生理和病理过程中发挥重要作用，然而其在青光眼神经损伤中的作用及分子机制尚未阐明。我们2014年发表在《PNAS》的研究结果表明，“caspase-8/NLRP3炎症小体”信号通路通过激活小胶质细胞促进炎症反应和细胞凋亡。前期研究及预实验发现，在急性青光眼模型中沉默lncRNA H19能够提高microRNA-21水平，降低PDCD4、caspase-8、NLRP3的表达，从而抑制节细胞死亡。本研究利用小鼠急、慢性青光眼模型，通过药物及基因工程等靶向调控手段，阐明“lncRNA H19/microRNA-21/PDCD4/caspase-8”介导的炎症及凋亡通路在青光眼神经损伤中的作用及分子机制，评估靶向治疗的应用前景，为青光眼治疗提供新的思路和理论依据。

青光眼（Glaucoma）是全球首位不可逆性致盲性眼病，以特征性视神经损伤和进行性视功能损害的为主要表现。据报道，截至2040年青光眼患病人数将增加74%，达到1.118亿人，给社会和家庭造成了沉重的负担。免疫机制是青光眼视神经继发性损伤的致病因素之一。长链非编码RNA (Long non-coding RNA, lncRNA) 过表达、缺失或突变可参与免疫细胞的激活和信号传递，可能在I/R损伤中发挥重要作用。我们采用稳定可靠的小鼠急性、激素性青光眼模型，验证了lncRNA H19/miR-21/PDCD4、lncRNA ANRIL/p15对青光眼的视神经保护作用，并且构建了全面的小鼠高眼压诱导的视网膜损伤的单细胞图谱，发现了靶向抑制铁死亡可有效保护视网膜结构及功能。上述研究结果对防止青光眼的发生、实现早期干预、判断疾病预后和寻找青光眼视神经保护新的靶向治疗具有十分重要的临床意义。