高眼压骤降激活TRPV4介导的“力-化学信号”转导致角膜内皮损伤的机制研究

角膜内皮具有维持角膜-房水屏障的重要功能，损伤后不可再生。当眼压显著升高时，角膜内皮损伤可源于高压态压迫或前房穿刺后的急性眼压骤降，但当前对后者的损伤机制尚不明确，更无法避免。我们依据多中心临床研究及动物实验结果提出假设：角膜内皮存在类似“缺血再灌注”等从异常微环境快速恢复后，损伤加重的现象，即高眼压快速降低相关的“高眼压骤降”损伤。我们也发现这一过程伴大量细胞凋亡，及压力敏感性通道TRPV4表达量显著增加。本申请拟从物理和生物化学角度，在分子、细胞和组织水平探究高眼压骤降致角膜内皮损伤过程中，前房流场突变这一应力启动后，TRPV4介导的“力-化学信号”转导引起细胞钙超载，进而通过下游PI3K/Akt信号通路调控细胞屏障结构，及通过细胞应激调控凋亡等具体机制，将为压力相关性角膜内皮病变提供潜在治疗靶点的同时，也为压力依赖性角膜内皮的体外构建提供理论参考，具有重要的科学意义。

TThe corneal endothelium is essential for the maintenance of cornea-aqueous barrier and it can’t regenerate after the injury. When the intraocular pressure increased significantly, the injury of corneal endothelial cells could be caused by itself or intraocular hypertension plunging after treatment. But the mechanism of the latter still remains unknown and inescapable so far. Based on multi-centric clinical study and preliminary animal experiment, we posit that corneal endothelium can be damaged further when intraocular hypertension is reduced to a normal level rapidly (intraocular hypertension plunging), which is similar to ischemia reperfusion. In this circumstance, pressure-sensitive ion channel TRPV4 is over expressed with lots of apoptotic corneal endothelial cells. So the current project will illuminate the mechanism of calcium overload in PI3K/Akt pathway regulating cellular barrier and cellular stress regulating apoptosis after flow field in the anterior chamber changing activates TRPV4-mediated mechano-chemical signal pathway on molecular, cellular and tissue levels from physical and biochemical standpoints during intraocular hypertension plunging. Our results will not only provide a potential therapeutic target for the treatment of pressure-related corneal endothelium injury, but also provide theoretical reference for in vitro construction of pressure-dependent corneal endothelium, which is of great significance.