过氧化物酶体增殖物激活受体α对青光眼视网膜神经节细胞的保护作用及机制的研究

The common pathway and the final outcome of glaucoma is selective and progressive death of retinal ganglion cells (RGCs). Growing evidence suggests that microcirculation disorder will induce hypoxia directly in optic papilla which can lead oxidative stress resulting in RGCs apoptosis. Peroxisome Proliferator-Activated Receptor α(PPARα) has been comfirmd as a key role in regulating inflammatory and oxidant activities. Recently, many studies demonstrated the beneficial effect of PPARα agonist on central nervous system disease through an anti-oxidant mechanism. However, the effect of PPARα on optic nerve in glaucoma was barely reported. We has firstly demonstrated the protective effect of PPARα on diabetic retinopathy and neuropathy by exerting anti-oxidant capability. We also found the change of PPARα expression in glaucomatous animal model. Therefore, we hypothesize PPARα plays a benificial role in glaucoma-induced RGCs apoptosis and optic damage in an anti-oxidant mechanism. In this study, we will firstly investigate the effect and the uderlying mechanism of PPARα as well as its agonist on glaucoma-induced RGCs apoptosis using glaucomatous cell and animal model, in order to develop the neuroprotection of glaucoma, provide new therapeutic gene target and drug method, enlight the future of glaucoma treatment.

视网膜神经节细胞(RGCs) 的选择性、进行性死亡是青光眼视神经损伤的共同通路和最终结局。近年来研究发现视乳头微循环障碍会直接导致视乳头缺血缺氧，从而引起RGCs氧化应激，诱导RGCs凋亡。有研究证实，过氧化物酶体增殖物激活受体α（PPARα）及其激动剂通过抑制氧化应激等机制对中枢神经性疾病具有一定的治疗作用，但其对于青光眼的视神经保护作用鲜有报道。本课题组率先发现PPARα通过抗氧化应激机制对于糖尿病视网膜血管病变和视神经病变具有显著保护作用，并且发现PPARα在青光眼中表达异常，因此提出假设PPARα可通过抗氧化应激机制抑制青光眼诱导的RGCs凋亡，从而对青光眼视神经损害具有保护作用。本项目拟通过细胞和青光眼动物模型，首次明确PPARα及其激动剂对RGCs凋亡的调控作用及机制，推动青光眼视神经保护研究的发展，为青光眼视神经保护提供新的治疗靶点和用药思路，为青光眼治疗带来新的希望。

视网膜神经节细胞(retinal ganglion cells，RGCs) 的选择性、进行性死亡是青光眼视神经损伤的共同通路和最终结局。近年来研究发现视乳头微循环缺血缺氧是导致RGCs凋亡的直接因素。我们前期成功以CoCl2诱导RGCs细胞缺氧构建青光眼细胞模型，诱导其发生凋亡，并以PPARα激动剂非诺贝特酸（Fenofibrate Acid， FA）干预细胞；我们发现FA显著抑制RGCs发生凋亡；之后我们构建PPARα过表达腺病毒重组载体并干预细胞，发现FA以及PPARα过表达腺病毒重组载体显著抑制RGCs的ROS的上调。我们还发现FA显著抑制RGCs中NOX4的表达上调，并且显著抑制NF-ĸB的活化。我们之后成功构建大鼠急性高眼压动物模型，然后以腹腔注射FA的方法来干预；我们发现FA显著抑制RGCs细胞凋亡的发生，并且抑制视网膜GFAP及NOX4等蛋白的表达上调。本项目为青光眼视神经保护治疗带来新的基因靶点和用药思路，为最终过渡到临床基因治疗打下坚实的理论和实践基础。

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