一氧化氮通过Peroxynitrite-PARP1通路引起眼压升高的作用和分子机制的实验研究

青光眼是引起不可逆致盲的第一位眼病，高眼压是青光眼的最危险因素。降低眼压是临床最有效的治疗青光眼的方法。高眼压主要是由于经典通路房水外流阻力增大造成的，NO供体的降压机制是降低经典房水外流通路阻力，因此降眼压效果强大。但是，NO长期持续使用反而会进一步增加眼压，从而限制了它的临床应用。NO的病理损伤作用主要通过peroxynitrite（PN）介导，PN又是如何作用，最终引起眼压升高，值得我们进一步研究。前期研究发现PN可能通过激活青光眼标志物PARP1，最终引起小梁网和Schlemm管内皮细胞功能障碍。因此，本项目将利用不同的细胞和动物模型，层层递进阐明NO过多首先生成PN，进一步激活PARP1，继而激活房水外流通路炎症因子，细胞连接蛋白，最终影响细胞功能，导致眼压升高。我们的研究结果将为NO的临床应用提供实验基础，并提出了两种新的青光眼降眼压靶点，PN和PARP1。

Glaucoma is the first cause of irreversible blindness of the eye disease, high intraocular pressure (IOP) is the most dangerous factor of glaucoma. Reducing IOP is the most effective clinical treatment for glaucoma. High IOP is mainly caused by the increase of conventional outflow resistance. The IOP lowering mechanism of NO donors is to reduce the conventional outflow resistance, and the effect is strong. However, long-term use of NO may further increase IOP, limiting its clinical use. The pathological damage effect of NO is mainly mediated by peroxynitrite (PN), and how PN acts and ultimately causes IOP elevation is worth further study. Previous studies have found that PN may cause trabecular meshwork and Schlemm canal endothelial cell dysfunction by activating the glaucoma marker PARP1. Therefore, this project will use different cell and animal models to illustrate step by step that excessive NO first generates PN, which further activates PARP1, and then activates inflammatory factors in the outflow pathway of aqueous humor, cell junction proteins, and finally affects cellular functions and leads to increased IOP. Our results will provide an experimental basis for the clinical application of NO, and propose two new IOP lowering targets for glaucoma, PN and PARP1.