外泌体源miR-125a调控TNF-α介导海洛因依赖者戒断期肠屏障损伤修复机制

海洛因依赖除可引起神经系统损害外，我们发现还可以引起肠屏障损伤，并导致严重感染，影响戒断效果，甚至死亡，但机制不明。TNF-α等炎症因子是引发肠道炎症的关键靶标，且受非编码RNA调控。我们预实验结果表明海洛因依赖者戒断期外泌体源miR-125a升高、TNF-α降低和肠上皮细胞损伤后的修复相关，生物信息学分析提示TNF-α是miR-125a的靶基因。我们提出假说：外泌体miR-125a调控TNF-α介导海洛因依赖者肠屏障损伤的修复。为验证上述假说，我们拟构建海洛因依赖细胞模型与灵长类动物模型，观察海洛因滥用、戒断及药物干预对细胞及动物模型肠上皮细胞损伤修复作用。在分子、细胞及动物水平探讨外泌体miR-125a和TNF-α的调控关系，进一步明确外泌体miR-125a调控TNF-α在海洛因依赖者肠屏障损伤修复的相关通路及可能的分子机制。为海洛因依赖者肠屏障损伤修复及引发的严重感染防治提供新视角。

Addiction was one of the majior characters of Heroin abuse, which also could cause nervous system damage, our previous study revealed that heroin could cause intestinal barrier injury and lead to serious infections, it also affected the withdrawal effect of heroin affection and even death. However, its mechanism was still unknown. Our previous works revealed that the increase of exsome miR-125a from immune cells during heroin withdrawal phase, decrease in TNF-α, which might assoctiated with the repair of intestinal mucosal epithelial cells. In view of the fact that TNF-a is the target gene of miR-125a, thus, we hypothesized that the miR-125a, an immune cell-derived exosome, might regulate the repair of intestinal barrier injury by TNF-α in heroin addicts. To verify this hypothesis, we intend to construct the co-culture model of human intestinal mucosa epithelial/immune cell and the heroin addiction primate model to investigate the affection of miR-125a and the recory of intestinal barrier injury during the during the stage of heroin abuse, withdrawal and drug intervention, and clarify the the relationships between exosome miR-125a and inflammatory cytokines TNF-α, and verify the potential pathyway of exosome miR-125a on regulating TNF-α during the recovery statge of intestinal barrier injury for heroin abuser and its possible molecular mechanisms. The results would provide a new perspective to repaire the intestinal barrier injury of heroin abuser.