Tm7sf2通过内质网应激调控小胶质细胞极化对脊髓损伤后脱髓鞘的作用及机制研究

小胶质细胞（MGs）极化在脊髓损伤（SCI）后脱髓鞘损伤中发挥重要作用，但对其极化规律和分子机制认识不足。本课题组基于前期研究及文献提出：SCI后Tm7sf2表达下降导致内质网应激（ERS）过度激活，进而上调MGs内炎症通路增强M1型MGs极化，最终加重脱髓鞘损伤。为此，本项目将：①首先确定SCI后MGs在时间和空间上极化规律；②借助特异性Tm7sf2敲除小鼠及细胞系证明SCI后Tm7sf2抑制将导致ERS过度激活、促进M1MGs极化并加重脱髓鞘损伤，揭示伤后“Tm7sf2-ERS-M1MGs极化-脱髓鞘损伤”轴的存在。③利用Cell Stress Array确定Tm7sf2下游靶基因即“ER源性M1诱导因子”，夯实损伤轴的分子机制。本项目首次把Tm7sf2调控ERS作为M1MGs极化的内在动因在SCI后脱髓鞘损伤中进行深入研究。这为SCI的治疗提供了全新靶点，具有重要的学术与临床价值。

Polarisation of microglia (MGs) acts an important role in demyelination after spinal cord injury (SCI). The pattern and molecular mechanisms, however, remain unclear. We propose based on our previous work and literature evidence that, the down regulation of Tm7sf2 after SCI induces overactivation of endoplasmic reticulum stress (ERS), up-regulates inflammatory responses and therefore promotes M1 polarisation. It ultimately deteriorates myelin damage. Hence, we will conduct following studies: ① to determine the temporal and spacial patterns of MGs polarisation after SCI. ② to examine the determinant role of Tm7sf2 in inducing ERS and M1MGs polarisation in post-SCI demyelination using MGstm7sf2-/- mice and cell lines. The hypothesis of “Tm7sf2-ERS-M1MGs-Demyelination” axis will the verified. ③ the downstream effectors of Tm7sf2, which is termed as “ERS-originated M1 inducers”, will be selected and confirmed by cell stress array. It is the molecular explanation of this study. Taken together, it is the first time that Tm7sf2-ERS is considered as an inner driver of M1MGs in post-SCI demyelination. It provides new insight and therapeutic target to treat SCI.