无长突细胞“NO-Zn2+”信号调控视神经损伤、修复及再生的分子机制

视网膜神经节细胞不可逆死亡是青光眼视神经损伤的根本原因，以节细胞或胶质细胞为靶点的传统疗法无法维持RGCs的长期存活并促进视神经再生，强烈提示仍存在未知的分子机制。团队前期研究成果（PNAS，2017）揭示游离态锌离子（Zn2+）在视神经损伤早期迅速升高并介导节细胞损伤，螯合剂治疗可使节细胞长期存活并重获轴突再生功能，但锌离子细胞来源及上游调控信号有待阐明。最新预实验结果提示视网膜中间神经元无长突细胞（ACs）内产生的一氧化氮（NO）是锌转化为游离态的关键信号。本研究将以青光眼视神经损伤动物模型为基础，利用新型特异性NO及锌离子探针，探寻ACs作为锌离子来源的确切证据，阐明青光眼视神经损伤过程中ACs的关键作用及“NO-Zn2+”信号调控分子机制，验证靶向治疗的安全性和有效性。本项目将为青光眼视神经损伤机制提供新的研究思路和理论依据，并为节细胞修复和视神经再生治疗提供崭新的细胞及分子靶点。

The irreversible death of retinal ganglion cells (RGCs) is the fundamental cause of optic nerve damage in glaucoma. Traditional therapies targeting RGCs or glial cells cannot either maintain long-term survival or promote optic nerve regeneration, strongly suggesting that unknown molecular mechanisms still exist. Preliminary results from us (PNAS, 2017) demonstrated that mobile zinc (Zn2+) increased rapidly after optic nerve injury and mediated delayed RGCs injury. Chelating Zn2+ prolonged the survival of RGCs and enabled optic nerve regeneration. However, the source of Zn2+ and the upstream signals still need to be clarified. Our latest preliminary results suggested that nitric oxide (NO) produced in one type of retinal interneurons, amacrine cells (ACs), is the key signal for Zn2+ release. In this study, based on the animal models of glaucoma and primary RGCs culture, we would like to investigate the crucial role of ACs in the pathogenesis of glaucoma neuropathy and the detailed mechanism of “NO-Zn2+” signaling pathway by using novel and highly-specific probes for NO and Zn2+, to explore the evidence of ACs as the cell-source of Zn2+ in the retina, and to verify the safety and efficacy of targeted therapies. This project will define a novel theoretical basis for the mechanism of glaucoma neuropathy and provide innovative cellular and molecular therapeutic targets for RGCs repair and optic nerve regeneration.