Müller细胞CD40/CD154共刺激信号通路对ATP-P2X7受体调节青光眼性视神经病变的作用及机制研究

青光眼视神经损伤的机制尚未完全阐明，视网膜最主要的胶质细胞-Müller细胞在其中的作用亟待深入探究。最新研究表明Müller细胞上的CD40/CD154共刺激信号通路在糖尿病视网膜病变及缺血再灌注损伤中对三磷酸腺苷（ATP）-P2X7受体介导的神经元损伤起关键作用。本课题组前期研究发现ATP-P2X7受体在青光眼视神经损伤中发挥重要作用，然而其上游通路尚未明晰。结合我们在慢性高眼压模型视网膜CD40表达升高的前期发现，我们提出了如下科学假说：高眼压致Müller细胞CD40/CD154通路激活，通过磷脂酶Cγ1致ATP释放，作用于视网膜小胶质细胞及视网膜神经节细胞（RGCs）的P2X7受体，导致炎性因子大量释放及RGCs死亡。本课题结合动物模型构建及细胞培养技术，运用组织学、分子生物学、生物发光、荧光探针等检测方法，对该假说进行实验论证，为青光眼性视神经病变的治疗提供崭新的靶点。

The mechanism of glaucomatous neuropathy is still not fully clarified. The role of Müller cells, the main retinal glia, needs to be explored. In recent studies on diabetic retinopathy and ischemia -reperfusion injury, CD40/CD154 costimulatory signal pathway in Müller cells was the key factor to ATP-P2X7 receptor caused retinal neuron injury. Our previous study found that ATP- P2X7 receptor played an important role in glaucomatous neuropathy. However, the upstream signal pathway was still unknown. Based on our study of CD40 upregulation in chronic glaucoma model, the hypothesis was put forward: High intraocular pressure activates Müller cell CD40/CD154 ligation, which triggers ATP release through PLCγ1 and P2X7 receptor activation in microglial cells and RGCs. This pathway promotes inflammatory cytokine production and RGCs death. The hypothesis will be studied through animal chronic glaucoma model construction and cell culture, combining histology, molecular biology, bioluminescence and fluorescence probe technique. This will provide new targets for glaucomatous neuropathy therapy.