创伤性脑损伤后GMFB促进星形胶质细胞激活的作用及机制研究

Astrocyte activation plays a key role in the pathogenesis of traumatic brain injury (TBI). We previously found in the zebrafish/mouse TBI model with GMFB gene knockout that GMFB is necessary for the activation of astrocyte after TBI. GMFB was expressed in microglia and astrocytes at the site of trauma. In microglia, GMFB promotes inflammatory activation of microglia. In astrocytes, GMFB promotes the activation of STAT3, a key transcription factor for astrogliosis. GMFB/STAT3 signaling axis promotes the production and secretion of LCN2, which is known to promote the activation of microglia and astrocytes. Therefore, GMFB may promote the activation of astrocytes after TBI through endogenous and exogenous pathways. We intend to study the role of GMFB in the subsequent activation of microglia and astrocytes after TBI, the activation mechanism of GMFB-STAT3-LCN2 axis in astrocytes, and whether LCN2 activates microglias/astrocytes. In vivo and in vitro methods such as primary cell culture and Stereotactic injection are used. The completion of this project will further reveal the important mechanism of astrocyte activation after TBI.

星形胶质细胞激活在创伤性脑损伤（TBI）发病中发挥关键作用。我们前期在GMFB基因敲除斑马鱼/小鼠TBI模型中发现，GMFB是TBI后星形细胞胶质化激活的必要条件；GMFB表达于创伤部位小胶质细胞和星形胶质细胞；在小胶质细胞中，GMFB促进小胶质细胞炎症性激活；在星形胶质细胞中，GMFB促进星形细胞胶质化关键转录因子STAT3激活，而GMFB/STAT3信号轴促进LCN2生成和分泌，LCN2已知可促进小胶质细胞和星形胶质细胞激活。由此推测，GMFB可能通过内源性和外源性途径促进TBI后星形胶质细胞激活。我们拟通过原代细胞培养、立体定向注射等体内外方法，研究GMFB在调控TBI后小胶质细胞和星形胶质细胞相继激活中的作用、星形胶质细胞中GMFB-STAT3-LCN2轴激活的机制、LCN2是否激活小胶质细胞/星形胶质细胞。本项目的完成将进一步揭示TBI后星形胶质细胞激活的重要机制。

我国TBI发病率与世界平均水平接近，由于我国人口基数庞大，导致TBI患病的绝对人数远超其它国家，对家庭和社会造成沉重负担。深入研究TBI发病机制对于改善TBI患者的治疗效果具有重要意义。.星形胶质细胞激活在创伤性脑损伤（TBI）发病中发挥关键作用。本研究发现GMFB基因敲除斑马鱼/小鼠TBI模型中发现，GMFB是TBI后星形细胞胶质化激活的必要条件；GMFB表达于创伤部位小胶质细胞和星形胶质细胞；在小胶质细胞中，GMFB促进小胶质细胞炎症性激活；在星形胶质细胞中，GMFB促进星形细胞胶质化过程中关键转录因子STAT3激活，而GMFB/STAT3信号轴促进LCN2生成和分泌，LCN2已知可促进小胶质细胞和星形胶质细胞激活。由此推测，GMFB可通过内源性和外源性途径促进TBI后星形胶质细胞激活。.TBI后星型胶质细胞的激活受到一系列内源性转录因子的调控，其中STAT3发挥了关键作用。TBI早期，创伤部位星型胶质细胞的胞质STAT3发生磷酸化激活、转位入核，继而上调众多下游基因的表达水平（其中包括胶质化标志性基因GFAP），共同促进星型细胞胶质化。我们课题组发现，TBI后2天，损伤周围的磷酸化STAT3水平上调，定位于星形胶质细胞，更重要的是，在GMFB基因敲除C57小鼠的TBI模型中，磷酸化STAT3水平在损伤周围上调减弱，这提示TBI诱导的STAT3磷酸化水平受到GMFB的正向调控。.GMFB对TBI后星形胶质细胞的胶质化过程至关重要，通过体外原代星形胶质细胞肌动蛋白骨架的解聚和聚合过程中发现，研究过程中发现GMFB促进其解聚和聚合过程。体内实验发现敲除GMFB可增加TBI后星形胶质细胞分支的复杂性，我们推测GMFB可能通过对细胞骨架的调控，改变了星状胶质细胞纤维丝的数量、形态与方向，进而影响了神经干细胞的分化，致使其神经再生功能降低。本项目的完成将进一步揭示TBI后星形胶质细胞激活的重要机制。