LINGO-1调控Lin28/Let-7信号轴在脑出血后抑郁发生中作用及机制研究

内囊再髓鞘化障碍是脑出血（ICH）后抑郁发生的关键因素。LINGO-1作为轴突再生和再髓鞘化负性调控枢纽分子，被认为是解决白质损伤后轴突和髓鞘相互抑制的关键切入点。近期发现Lin28/let-7信号轴对再髓鞘化进程具有重要调控作用，但上游机制不详。我们前期研究证实ICH内囊损伤后，Papez环轴突LINGO-1表达持续上调，同时少突胶质前体细胞（OPCs）内Lin28/Let-7信号轴激活，而LINGO-1单抗治疗可减少ICH动物抑郁样行为。据此推测：ICH后血肿代谢产物持续激活轴突LINGO-1，其胞外域跨细胞作用于OPCs内Lin28/let-7信号轴，抑制再髓鞘化，从而导致ICH后抑郁发生。本课题拟于动物及分子层面上探究轴突LINGO-1通过OPCs内Lin28/let-7信号轴，影响ICH后再髓鞘化的作用机制，进而实现内囊白质功能性重建，为ICH后抑郁的防治提供新的干预靶点。

The disorder of internal capsule remyelination is the major contributing factor to the post-intracerebral hemorrhage depression. As the crucial negative regulatory factor, LINGO-1 was considered a key cut-in point to solve the mutual inhibition of axon and myelin after white matter injury. Recently, it has been found that the process of remyelination was controlled by Lin28/Let-7 signal axis, but its upstream mechanism still remained unclear. The results of our preliminary studies showed that the expression of axonal LINGO-1 in Papez circuit was sustained up-regulated and the Lin28/Let-7 signal axis in oligodendrocyte precursor cells (OPCs) was activated after intracerebral hemorrhage (ICH). Additionally, the ICH animals which was treated by the LINGO-1 monoclonal antibody showed reduced depression-like behaviors. Presumably, the axonal LINGO-1 is sustained activated by the metabolites of hematoma after ICH, then exerts a transcellular effect on the Lin28/Let-7 signal axis in the surrounding OPCs, and then inhabits the remyelination of internal capsule which led to post-ICH depression. Our project intends to explore the influence of the activation of axonal LINGO-1 on the remyelination after ICH from the animal and molecular levels, so as to realize the functional reconstruction of the injured internal capsule and provide a novel target for intervention for the post-ICH depression.