调控RAGE基因在青光眼视神经保护中的作用和机制研究

Glaucoma, the second blindness-inducing disease worldwide, is a neurodegenerative disease of the eye. With the basic pathogenesis of progressive loss of retinal ganglion cells (RGCs) and their axons, the neurodegeneration in glaucoma goes through two phases: the direct damage to RGCs and the secondary damage by responses of non-neuronal cells in the microenvironment. The secondary damage is considered as the major cause of RGC loss in glaucoma. In our previous study, we found the "neurovascular unit" played roles in the mechanism of RGC degeneration through damage of blood-retinal-barriers and over-activation of glial cells in glaucoma mouse model.Together,we also detected the strong immunoreactivity of RAGE (receptor of advanced glycation end products) in these ocular-hypertensive retinas. Thus, in this study, we hypothesized that RAGE maybe play roles in damaging the "neurovascular unit" and induce the dysregulation of retinal blood vessels and retinal glial cells, by activating its multiple ligands with their related signaling pathways, resulting in the secondary damage to RGCs. Since we had already detected the over-expression of RAGE immunosignals not only on blood vessel endothelial cells, retinal glial cells but also on RGCs. This finding also suggested that mediating RAGE signaling pathway maybe have neuroprotective effects on RGCs. Thus, in this study, using ocular-hypertensive mice, we will 1) detect the time course of RAGE signaling pathways on retina, 2) block RAGE by siRNA to observe the effects on retinal cells (retinal neurons, blood vessel endothelial cells and glial cells), and 3) test the electric signal changes of optic nerve and evaluate visual behavor of these animals to investigate the effect of mediating RAGE on the neuroprotection of glaucoma. Based on this study, we would propose a new concept- - "microenvironmental protection" to be a promising therapeutic intervention for neuroprotection of glaucoma.

视网膜节细胞(RGC)的间接性损伤在青光眼视神经病变中有明确的致病作用，但其确切机制尚未明确。本课题拟在申请人以往对"神经血管单元"在青光眼RGC损伤机制中作用的研究基础上，提出假设：在神经血管单元的作用下，糖基化终末产物受体(RAGE)可能通过与多配体结合引起相关信号系统激活，导致血管内皮和胶质细胞功能障碍，在RGC的间接性损伤机制中发挥致病作用。因此，本课题拟①检测高眼压模型小鼠RAGE基因及其配体信号的表达以明确其在视网膜上的分布及随时间的变化。②阻断RAGE来观察其信号系统对视网膜血管内皮细胞，胶质细胞及RGC的影响。③观察RAGE阻断治疗对高眼压小鼠的视神经电生理信号和视觉行为学的变化，以验证调节RAGE信号系统是否对青光眼视神经损害起保护作用。本研究旨在为"内环境保护"这一青光眼视神经保护治疗提供直接实验依据，并为今后临床青光眼的早期干预治疗提供新思路。

视网膜节细胞(RGC)的间接性损伤在青光眼视神经病变中有明确的致病作用，但其确切机制尚未明确。本课题拟在申请人以往对“神经血管单元”在青光眼RGC损伤机制中作用的研究基础上，主要研究内容：在神经血管单元的作用下，糖基化终末产物受体(RAGE)可能通过与多配体结合引起相关信号系统激活，导致血管内皮和胶质细胞功能障碍，在RGC的间接性损伤机制中发挥致病作用。重要结果：1. 稳定建立出高眼压小鼠动物模型。2.利用micro-circulating RAGE分子（对RAGE信号有竞争性阻断作用），发现阻断RAGE对小鼠高眼压视网膜上的视神经节细胞有保护作用。3. 阻断RAGE可以调节高眼压损伤中胶质细胞反应。4.RAGE阻断治疗提高了高眼压损伤下小鼠视网膜视神经电生理信号和视觉行为学得分，验证了调节RAGE信号系统对青光眼视神经损害起保护作用。本研究目前已发表相关论文多篇，为今后临床青光眼的早期干预治疗提供了依据。