如何促进脑梗死后运动功能的重建是目前临床治疗的难点。本课题组前期研究发现，脑梗死后患侧皮层受多重组织损害机制影响，严重影响了神经功能恢复，而健侧运动皮层神经重塑重建了上下运动神经元之间的联系并促进运动功能恢复，因此被认为可能是个潜在的干预靶点。关键转录因子过表达可在体内重编程神经元，但能否通过重编程的方式增加梗死后健侧皮层皮质脊髓运动神经元的数量，实现神经网络重建和功能代偿目前尚不清楚。本项目拟采用CaMKIIα-CreER转基因小鼠建立脑梗死模型，用AAV腺相关病毒构建调控皮质脊髓运动神经元分化的关键因子Fezf2表达载体，将Ⅱ/Ⅲ层胼胝体投射神经元重编程为皮质脊髓运动神经元，鉴定重编程神经元的形态学、表观遗传学和电生理特性并计算出转化率，解析其能否诱导中间神经元构建新的神经网络，评估其对神经功能症状的改善效果，进而探讨其可能的分子机制，为寻找脑梗死治疗新靶点和新策略提供实验依据。

Neuronal regeneration and motor function reconstruction after ischemic infarction are hot spots of present research. In our previous study, we found out that multiple damaging mechanisms hindered rehabilitation process in the infarcted hemisphere. However, remodeling of the contralesional hemisphere accompanied by reconnecting the disconnected fibers, are correlated to motor function recovery. Lineage reprogramming, which can be defined as direct conversion of specific differentiated cell type into another lineage, has been a potential approach for producing neurons. However, whether reprogramming neurons could contribute to functional recovery after ischemic infarction has not been reported. Therefore, we plan to apply a CaMKIIα-CreER transgenic mouse model of ischemic infarction, and use direct reprogramming of callosal neurons into coticofugal neurons by force expression of Fezf2, which is an intrinsic master gene capable of instructing identity of corticospinal motor neurons. The properties of induced corticospinal motor neurons will be determined by using a combination of morphological, molecular, eletrophysiological and ultrastuctural imaging approaches. To test whether induced corticospinal motor neurons could reshape the local neocortical microcircuit, patch clamp recordings will be performed. By investigating the underlying molecular mechanisms, our study may provide an experimental basis for a novel interventional target and a promising approach to cure ischemic infarction.