大气细颗粒物通过NF-κB/LBP-9信号通路诱导小胶质细胞激活加剧CNS脱髓鞘损伤的作用机制研究

大气细颗粒物PM2.5污染与脱髓鞘疾病的发展密切相关，但致病机制不清。我们前期研究发现小胶质细胞激活在PM2.5促髓鞘损伤中起关键作用，LBP9是介导PM2.5效应的特异表达基因，但其在小胶质细胞活化中的功能及信号转导机制未知。由于PM2.5的作用依赖于NFκB，LBP9启动子有保守的NFκB位点，我们提出PM2.5通过NFκB/LBP9信号轴诱导小胶质细胞激活加剧髓鞘损伤的机制假说。本课题将借助细胞特异性遗传操作和定向移植技术，明确PM2.5促髓鞘损伤的细胞基础（小胶质细胞）和特异效应基因（LBP9）；进而通过ChIP-PCR、功能阻断/恢复实验，解析LBP9作为NFκB靶基因参与PM2.5诱导小胶质细胞激活的分子机制；最后利用脱髓鞘及髓鞘生成动物模型，系统评估靶向干预LBP9对PM2.5促髓鞘脱失的治疗作用。研究结果可为阐明PM2.5加剧脱髓鞘损伤的致病机制、筛选治疗靶点提供理论依据。

Atmospheric fine particulate matter (PM2.5) plays a critical role in the development of demyelinating diseases. However, the pathogenic mechanism remains unclear. In the previous study, we found that microglia activation is an important cause of PM2.5-induced exacerbation of myelin injury. LBP9 is a specifically expressed gene that responses to the PM2.5 stimulation, but its function and signal transduction in microglia activation is unknown. Given the impacts of PM2.5 is dependent on NFκB activation, and LBP9 promoter contains conserved NFκB binding domain, we thus hypothesize that PM2.5 induces microglial activation to aggravate CNS demyelination through NFκB/LBP9 signaling axis. In this proposal, we will firstly clarify the cytological basis (microglia) and specific responser (LBP9) of PM2.5 on exacerbating CNS demyelination, based on the cell-specific genetic manipulation and stereotaxic transplantation techniques. Then we will further elucidate the molecular mechanism of LBP9, as the NFκB target gene, involved in PM2.5-induced microglia activation, using CHIP-PCR and functional blocking/rescue assays. From the therapeutic angle, we will test the effects of LBP9 conditional deletion in microglia for the relief of PM2.5-induced demyelinating injury, based on using three demyelination/myelinogenesis animal models. This project, if successful, will elucidate the pathogenic mechanism of PM2.5-aggravated demyelinating diseases, and provide a new therapeutic target for the prevention and treatment of such diseases.