维生素K通过上调小梁细胞MGP表达增加小梁网房水排出的机制研究

小梁细胞发生病理性钙化，导致细胞外基质病变及小梁网硬度升高是房水外流阻力增加的关键因素。小梁细胞表达维生素K依赖性蛋白-基质Gla蛋白(MGP)，通过抑制BMP2信号通路调控小梁网钙化。青光眼患者小梁网MGP表达下降、钙化增加，但其具体机制不明。申请人发现，开角型青光眼患者血浆维生素K水平低下，小梁网MGP表达下降，出现病理性钙化。高维生素K1饮食可促进青光眼模型鼠小梁网MGP表达增加，眼压降低，显著减少视网膜神经节细胞的凋亡。据此假设，维生素K可通过提高小梁网MGP的表达、抑制BMP2信号通路及小梁网钙化，改善青光眼患者房水外流阻力。本项目将利用MGP敲除模型鼠和腺病毒转染后小梁网高表达MGP的模型鼠，阐明MGP是维生素K抑制小梁网钙化和增加小梁网房水排出的关键作用靶点。利用原代小梁细胞青光眼模型，探究维生素K对小梁细胞钙化和MGP-BMP2信号通路的作用，为青光眼干预治疗提供新思路。

Pathological calcification of trabecular meshwork cells, which leads to the changes of extracellular matrix and the hardness of trabecular meshwork, is the key factor for the increased aqueous outflow resistance in trabecular meshwork (TM). TM cells express vitamin K-dependent protein-matrix Gla protein (MGP) and regulate the calcification of TM by inhibiting BMP2. The expression of MGP in TM is decreased and calcification is increased in glaucoma patients, but the underlying mechanism is unclear. The applicant found that patients with open-angle glaucoma had low vitamin K level in the plasma, and had decreased expression of MGP and increased pathological calcification in TM. High vitamin K1 diet can lead to increased MGP expression in TM, decreased intraocular pressure, and significant reduced apoptosis of retinal ganglion cells. According to these studies, we hypothesize that vitamin K can improve the aqueous outflow of TM in glaucoma patients by improving the expression of MGP, inhibiting the BMP2 signaling pathway and reducing calcification in TM. This project will use MGP knock-out model mice and model mice with high expression of MGP in TM after adenovirus transfection to clarify that MGP is a key target for vitamin K to inhibit TM calcification and increase aqueous outflow of TM. In vitro glaucoma model was used to explore the effects of vitamin K on TM cell calcification and MGP-BMP2 signaling pathway, aiming to provide new targets for the intervention and treatment of glaucoma.