脑外伤（TBI）后继发性损害是造成神经细胞死亡和神经功能障碍的主要原因。TBI引起线粒体膜破坏导致继发性细胞死亡已被深入研究，TBI引起自噬激活也已被证明，但急性线粒体损伤的神经细胞是否可修复、线粒体损伤与自噬激活是否存在相互调节及其对TBI后细胞死亡及神经功能障碍的作用等问题仍未知。本项目在我们多年研究TBI后神经细胞死亡及自噬机制的基础上，分别建立体内和体外TBI模型，以最新发现的能够介导线粒体裂解过程的Drp1作为靶点，研究如下：①证明Drp1参与了TBI后神经细胞内线粒体的损害过程；②运用Drp1抑制剂mdivi-1或RNA干扰技术，在体内和体外分别研究Drp1在TBI后神经细胞损伤中的作用及机制；③研究Drp1对TBI后自噬流的影响以及抑制自噬对Drp1表达、线粒体形态及神经细胞损伤的影响。上述研究最终将证明抑制Drp1介导的线粒体损害并有效调节自噬流是临床治疗TBI的重要靶点。

Acute membrane damage due to traumatic brain injury (TBI) is a critical precipitating event that leads to nerve cell death and neurological dysfunction. TBI-induced mitochondrial membrane damage that leads to secondary cell death has been extensively studied, and autophagy activation induced by TBI has also been proven. However, whether the nerve cells which meet acute mitochondrial damage could be repaired, whether mutual regulation between mitochondrial damage and autophagy exists, and the effects on nerve cell death and neurological dysfunction, together with other issues after TBI are still unknown. Base on many years that we study the nerve cell death and autophagy mechanism, this project was to establish TBI model (in vivo and in vitro) and base on a newly discovered regulatory protein Drp1 as a target that mediated mitochondria fission to study the issues as follows: ①to prove Drp1 involved in the process of mitochondria damage in nerve cells; ②using Drp1 inhibitor mdivi-1 or RNA interference, to study the effects of Drp1-mediated mitochondria fission on nerve cell damage in vivo and in vitro after TBI, and its mechanism; ③to study the effects of Drp1 on the flow of autophagy after TBI, and the effects of autophagy inhibition on Drp1 expression, mitochondrial morphology and nerve cell damage. The study will ultimately prove that, to inhibit Drp1-mediated mitochondrial damage and to regulate autophagy flow effectively are an important target for clinical treatment of TBI.