靶向调控RIP3/Nrf2/Beclin-1维持自噬稳态干预视神经损伤的作用研究

神经节细胞的变性死亡是视神经损伤疾病的核心环节，调控细胞存活是视神经保护和损伤修复的重要策略。我们前期研究证实蛋白激酶RIP3介导的神经细胞程序性坏死促进视网膜损伤与变性过程（Cell Death Differ 2018）。新近研究提示RIP3在特定环境下还可诱导细胞自噬，具体机制不清。我们发现视神经损伤早期，神经节细胞同时高表达RIP3和Beclin-1触发自噬稳态失衡，由此提出“RIP3活化诱导神经节细胞自噬性死亡，加重视神经损伤”的科学假说。拟利用多种疾病模型、基因敲除鼠、单细胞测序等在体内外水平研究：1）RIP3介导的神经节细胞自噬稳态失衡在视神经损伤中的作用；2）RIP3激活Nrf2/Beclin-1诱导自噬性死亡的分子机制；3）靶向调控RIP3通路干预视神经损伤的安全性和有效性。研究成果将进一步明确神经细胞自噬的调控机制，探索有效干预靶点，为视神经损伤疾病的治疗提供新策略。

Neuronal degeneration and death is the core pathological process of optic nerve injury. Modulation of cell death signaling and neuroprotection have gained intensive attention in recent decades and appears to be a potential therapeutic strategy. We previously found that necroptosis in retinal microglia contributed to retinal degeneration via the receptor interacting protein 3 (RIP3) signaling. Recent studies revealed a potential role of RIP3 in cell autophagy, however, with its exact mechanism remained unclear. Our preliminary data showed elevated levels of RIP3 as well as the key autophagy-related protein Beclin-1 in retinal ganglion cells (RGCs) in an optic nerve injury murine model, indicating a potential role of RIP3 in RGC autophagy. Based on our data and recent findings of others, we hypothesize that RIP3 activation could regulate Nrf2 and increased Beclin-1 expression, leading to RGC autophagic cell death and optic nerve injury. We aim to demonstrate the role RIP3-mediared RGC autophagy and its underlying molecular mechanisms in optic nerve injury using various disease models, gene knock-out mice and single cell sequencing. In addition, the neuroprotective effect of RIP3/Nrf2/Beclin-1 blockade using specific RIP3 inhibitor GSK will be explored. The results may broaden the insight in regulation of neuronal death and present an attractive strategy for the treatment of neural nerve injury diseases.