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

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.

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。

本研究立足于前期研究基础，通过干预Lin28/Let-7通路中的关键分子，探讨轴突Lingo-1在脑出血引起的白质功能损伤中的作用，为脑出血后抑郁的临床治疗提供实验证据。.1.首次证实了Lin28/Let-7通路在脑出血后的早期脑损伤的发生发展过程中发挥重要的调节作用。运用Lingo-1单抗以及Lingo-1 shRNA后可以显著改善ICh后大鼠抑郁样行为，减少神经元损伤、减轻脑水肿、改善血脑屏障渗透性、减少白质损伤 。其机制可能与激活Lin28/Let-7通路和抑制微管结构的降解有关。抑制轴突Lingo-1表达可能成为减轻ICH后早期脑损伤的重要靶点。.2.阐明脑出血后抑郁的发生与轴突微管蛋白解聚所导致的黑质区多巴胺能神经元损失及多巴胺含量降低密切相关，并首次发现埃博霉素可用于稳定轴突微管蛋白结构，从而显著减轻实验动物的脑出血后抑郁样行为的发生。.3.揭示下丘脑PO/AH区温敏神经元上的5-HT1a蛋白可作用内源性压低温的作用靶点，应用其特异性激动剂8-OH-DPAT可诱导化学性压低温效应，有效减轻ICH后白质功能损伤，促进髓鞘再生，并减轻血脑屏障的破坏。