LncRNA NEAT1-FOXO3信号轴在Fuchs角膜内皮营养不良中的作用和机制研究

Fuchs内皮营养不良(FECD)是角膜内皮功能失代偿的常见病因，角膜移植是其目前唯一治疗手段，其机制尚未完全明确。前期我们通过人角膜内皮单细胞和普通转录组测序分析，结合功能实验发现：（1）长链非编码RNA NEAT1在正常角膜内皮中高表达，但在FECD患者和小鼠模型中显著下降；（2）FECD小鼠模型中，干扰Neat1会加重角膜内皮损伤程度，而过表达可缓解损伤症状；（3）NEAT1可正向调控关键抗氧化因子FOXO3的表达，影响角膜内皮细胞的抗氧化能力。由此提示，NEAT1可通过FOXO3调控角膜内皮细胞的氧化还原稳态，进而影响FECD的发生发展。因此，本课题拟结合细胞氧化损伤模型、FECD动物模型和敲除小鼠，明确NEAT1在FECD发病过程中的具体功能，阐明NEAT1-FOXO3信号轴参与调控角膜内皮细胞氧化应激反应和FECD发生发展的作用机制，为临床诊断和干预提供新的研究思路和潜在靶点。

Fuchs endothelial corneal dystrophy (FECD) is a common cause of corneal endothelial functional decompensation, and corneal transplantation is the only way to restore vision loss in FECD patients, but its mechanism is not fully understood. In preliminary studies, based on the single-cell and bulk transcriptomic analysis of human corneal endothelia and functional assays, we found that: (1) The long non-coding RNA (lncRNA) NEAT1 were highly expressed in normal corneal endothelium, but significantly decreased in FECD patients and mouse models; (2) Knockdown of Neat1 exacerbated the damage of mouse corneal endothelium, while overexpression diminished the symptoms of corneal endothelial injury; (3) NEAT1 could positively regulate the expression of the key antioxidant factor, FOXO3, then affected the antioxidant ability of corneal endothelial cells. It indicated that NEAT1 might regulate the cellular redox homeostasis of corneal endothelium by targeting FOXO3, and then affected the occurrence and development of FECD. Therefore, this project intends to combine cellular oxidative damage models, FECD animal models and Neat1 knockout mice to clarify the functional role of NEAT1 in the pathogenesis of FECD, and the molecular mechanism of NEAT1-FOXO3 axis in regulating oxidative stress response of corneal endothelial cells as well as the occurrence and progression of FECD, providing new ideas and potential targets for clinical intervention.