脱髓鞘性损伤是多种神经系统疾病共有的病理特征，少突胶质前体细胞(OPC)分化是髓鞘再生的细胞基础和治疗靶点。我们前期研究发现黄芩苷通过激活转录因子NFIL3有效促进髓鞘修复，但黄芩苷和NFIL3在OPC分化中的作用及信号转导机制未知。由于黄芩苷可靶向激活核受体PPARγ，而NFIL3启动子区有PPAR的结合位点，我们推测，黄芩苷通过调控PPARγ/NFIL3信号通路促进OPC分化。本项目拟采用萤光素酶报告基因法、CHIP-PCR、点突变和功能拮抗/恢复实验，明确黄芩苷对PPARγ/NFIL3的靶向调控机制；进而通过NFIL3过表达/缺失/条件型降低的脑片培养及脱髓鞘模型，揭示黄芩苷依赖NFIL3促进髓鞘再生的直接作用；最后利用CP-和RR-EAE模型，系统评估黄芩苷及其调控的NFIL3对脱髓鞘疾病的治疗效果。研究结果可为髓鞘损伤修复提供有效的候选药物(黄芩苷)和新的治疗靶点(NFIL3)。

Demyelination is the common pathological features of several neurological disease. Oligodendrocyte precursor cell (OPC) differentiation is the cytological basis and therapeutic targets of remyelination. In the previous study, we reported that baicalin is effective in promoting myelin repair in an NFIL3-dependent manner, while the function of both baicalin and NFIL3 in myelination is unknown. Given the activation effect of baicalin on peroxisome proliferator-activated receptor gamma (PPARγ), which can bind multiple peroxisome proliferator elements (PPRE) in the promoter sequences of NFIL3, we thus hypothesize that the therapeutic effect of baicalin on remyelination is mediated by PPARγ/NFIL3 signal pathway. In this proposal, we will firstly elucidate the regulation mechanism and target genes underlying the induction of PPARγ/NFIL3 signal pathway by baicalin, using dual luciferase reporter assay, CHIP-PCR, site-directed mutagenesis and functional blocking/rescue assays. Then we will test the direct effects of baicalin on OPC differentiation and remyelination, and the role of NFIL3 in this process, based on the in vitro and in vivo demyelinating models. From the therapeutic angle, we will test the NFIL3-mediated therapeutic effects of baicalin on the chronic stage of chronic-progressive (CP) and relapsing-remitting (RR) EAE. This project, if successful, will provide findings confirming baicalin’s potential as a novel therapy for demyelinating disease and will elucidate the mechanisms underlying its action.