高眼压损伤后视网膜神经节细胞易损性增加的机制研究

High intraocular pressure (IOP) induced retinal ganglion cell (RGC) damage and apoptosis is the key basis for the pathogenesis of glaucoma, a major blinding desease worldwide. A complete understanding of the rules and characterisitics of high IOP induced neuropathy would be beneficial to an improved clinical efficacy of glaucoma management. In our previous studies, we have found that glaucomatous neuropathy leads to visual field defect and up-regulation of P75NTR recepters and higher vulnerability in remaining RGCs. Our hypothesis in this study is that, when high IOP induced RGCs damage happens, visual defects resultant from RGCs apoptosis may lead to impaired cortical excitement and consequent decrease in synthesis of brain derived neurotrophic factors (NT) in the brain, which are vital for the survival of neuronal cells in the visual pathway including RGCs. On the contrary, pro-NTs accumulate in the visual cortex and can be shipped to remaining RGCs through axoplasmic transport. Combining of pro-NTs and P75NTR recepter results in enhanced vulnerability in surviving RGCs. This coincides with frequent clinical phenomenon that "the more severe the glaucomatous neuropathy, the more increased vulnerability in the remaining RGCs, and the lower target IOP required for the treatment ". In this project, we want to validate this hypothesis in high IOP rat models.

高眼压所致视网膜神经节细胞（RGCs）损伤、凋亡是主要致盲眼病青光眼发生的病理生理基础。明确高眼压RGCs创伤的机制和规律，将有助于提高青光眼的诊治效率。我们在前期研究中发现，高眼压性RGC损伤和视野缺损后，视觉中枢内功能活动降低，RGCs表面的p75NTR受体表达上调，残余RGCs的易损性增加。本项目的假说是：高眼压导致RGCs创伤和视野缺损后，视觉中枢内神经元兴奋减弱，中枢神经元内神经营养因子前体（pro-NT）不能被水解、合成RGCs赖以生存的神经营养因子（NT）；相反，中枢内蓄积的pro-NT可通过轴浆流运输与RGCs表面的p75NTR受体结合，导致残余的RGCs易损性增加，使其对眼压和其他病理因素的耐受性降低。这与临床上，高眼压损害越重，残余RGCs对眼压的耐受性越低相吻合。本项目拟采用大鼠高眼压视神经创伤模型对该假说进行验证。