NF155在缺氧缺血脑白质损伤髓鞘形成障碍中的作用及机制

The primary pathological change of neonatal hypoxic ischemic cerebral white matter injury (HI-CWMI) is dysfunction of axon myelination,the mechanism has not been clarified. Neurofascin 155 (NF155) is produced by oligodendrocytes (OL) and mainly distributed in lipid rafts of myelin paranode, and plays very important role in myelin formation and its stabliztion. Our previous research found that the expression of NF155 significantly decreased in HI-CWMI rat brains. Promoting the binding of NF155 with lipid rafts can stabilize the structure of paranodes, and eventually prevent myelin sheath damage. It was recently found that NF155 has a ERM binding motif. ERM-RhoGTP enzyme pathway is an important pathway to regulate OL’s cytoskeleton, suggesting that NF155 may be involved in the regulation of OL cytoskeleton. We hypothesized that reduced NF155 expression in perinatal HI-CWMI decrease paranodal formation and influences assemble and transportation of OL cytoskeleton via ERM-RhoGTPas signal channel. So, with gene transfection and other techniques, we'll observe the high expression of NF155 on the cytoskeleton of oligodendrocyte, explore its mechanism in HI-CWMI vitro model.The results will be helpful for a better understanding of the pathogenesis of HI-CWMI.

新生儿缺氧缺血性脑白质损伤（HI-CWMI）的主要病变是轴突髓鞘化障碍，其机制尚不清楚。神经束蛋白155（NF155）由少突胶质细胞（OL）产生，主要分布于髓鞘结侧区的脂筏中,是髓鞘化过程中的重要蛋白。前期发现HI-CWMI大鼠脑NF155减少，通过修复脂筏可增加结侧区NF155并修复髓鞘，提示其参与了HI-CWMI髓鞘化障碍的进程。新近发现NF155具有ERM结合基序, 而ERM-RhoGTP酶信号通路是调节OL细胞骨架以完成髓鞘化的重要通路。我们推测，HI-CWMI后由于脑NF155表达下降使ERM-RhoGTP酶信号通路激活受阻，影响OL细胞骨架组装，导致髓鞘化障碍。为此，本课题拟采用离体HI-CWMI模型，通过基因转染使NF155表达高表达，观察其对HI-CWMI模型OL细胞骨架的影响，探索HI-CWMI髓鞘化障碍的新机制及开辟干预新途径。

围产期缺氧缺血造成的早产儿脑白质损伤是早产儿最常见的脑损伤类型，以髓鞘减少或髓鞘形成障碍为主要病理特征，但其病理生理机制尚未完全阐明。神经束蛋白155（NF155）与髓鞘的形成和发育密切相关，研究提示NF155还可能与成髓鞘细胞的细胞骨架演变有关，我们前期研究亦提示NF155参与了缺氧缺血脑白质损伤中髓鞘发育障碍的病理机制。因此我们推测，如能在胶质细胞受到缺氧损害的早期提高NF155的表达，有望促进髓鞘发育的正常化，进而改善神经功能。为此，本研究建立了新生大鼠前脑混合细胞缺氧缺血培养体系，通过瞬时转染过表达NF155，发现NF155与髓鞘发育的相关蛋白MBP、caspr、contactin，以及参与细胞骨架调节的Rho GTP酶家族的Rac1、Cdc42均有协同相关性作用；随着NF155及相关蛋白的表达恢复，髓鞘细胞骨架蛋白及组装得以恢复，轴突结构清晰透明，髓鞘修复再生和功能恢复。我们的研究以NF155为切入点，为缺氧缺血性脑白质损伤的发病机制提供了一种新的见解，期待为缺氧缺血性脑白质损伤的干预提供新的可能。