Plin2介导的脂噬障碍在继发性脊髓损伤中的作用及机制研究

脊髓损伤严重危害患者生存质量，目前无有效治疗措施。我们观察到损伤局部的神经元内出现大量脂滴蓄积，伴多种有害脂质增多。该现象尚未被充分认识，可能是导致继发性脊髓损伤的重要因素之一。前期研究发现Plin2在损伤局部显著升高。该分子被认为对细胞自噬水平有抑制作用，并能直接阻碍特异性自噬（脂噬）对脂滴的识别。因此我们推测升高的Plin2通过抑制脂噬活性和干扰自噬体-脂滴结合的双重作用导致有害脂质蓄积，引起神经元死亡。本研究拟通过脂质组学技术，分析脊髓损伤后局部脂质成分的变化；通过干扰Plin2表达，明确其影响脂噬的机制；应用条件性Plin2敲除小鼠，探究Plin2作为脊髓损伤治疗靶点的可能性。本研究创新性地使用受激拉曼散射成像技术，无需荧光标记，实现活体脊髓内脂质水平的检测，为脂代谢在体研究提供巨大便利。通过本项目能深入阐明脂噬及脂代谢异常在继发性脊髓损伤中的作用，为临床干预提供新思路。

Having no effective treatment, spinal cord injury (SCI) negatively impacts patients’ quality of life seriously. Although not substantiated, large quantity of lipid droplets accumulation in injured spinal cord neurons, accompanied by an increase of various harmful lipids observed in a previous study may play an important role in secondary spinal cord injury. We also found via high-throughput sequencing that Plin2 significantly increased around the lesion area after SCI. Plin2 has been reported to have an inhibitory effect on cell autophagic activity and can directly prevent lipid droplet-specific autophagy (lipophagy) from recycling lipid. Therefore, we formulate a hypothesis that elevated Plin2 results in the accumulation of harmful lipids through the dual effect of inhibiting lipophagic activity and interfering with the binding of autophagosomes to lipid droplets, eventually leading to secondary neuronal death. This study aims to analyze the changes of lipid components after SCI, and explain the possible mechanism of Plin2 affecting lipophagy by interfering the expression of Plin2. The therapeutic value will be explored on a Plin2 conditionally knock-out mice model. Our study innovatively uses stimulated Raman scattering (SRS) imaging technology to detect the lipid level of spinal cord in-vivo, which requires no fluorescent labeling and provides great convenience for the in-vivo study of lipid metabolism. The implementation of this project can further clarify the role of lipophagy and abnormal lipid metabolism in secondary spinal cord injury, and may provide new idea for clinical intervention.