多发性硬化（MS）与CNS胆固醇代谢失衡有关。由于血脑屏障的存在，脑内胆固醇需要依赖CYP46A1代谢后才可消除。通常情况下，CYP46A1主要分布于神经元，在神经病变刺激下，CYP46A1在神经脱髓鞘部位的神经胶质细胞中表达增加，提示CYP46A1可能是参与了MS脱髓鞘过程。此外，我们发现CYP46A1在LPS诱导的小胶质细胞株BV-2中表达，同时干扰CYP46A1可能通过Nrf2改善LPS诱导的氧化应激指标。我们根据已有研究结果提出来CYP46A1在MS中通过抑制Nrf2/ARE抗氧化通路导致小胶质细胞激活的假说，拟采用原代小胶质细胞、实验性自身免疫性脑脊髓炎（EAE)模型，结合腺相关病毒过表达、shRNA干扰、PET/CT、免疫荧光、免疫共沉淀等方法，旨在证实我们的假说，并进一步从CYP46A1与Nrf2、Keap1相互作用研究调控机制，为干预治疗MS提供理论依据。

Multiple sclerosis (MS) is correlated with the imbalance of CNS cholesterol metabolism. Due to the blood brain barrier, brain cholesterol has to be metabolized by CYP46A1 before elimination. CYP46A1 is normally distributed in neurons, however, it is increased in glia cells from the positions of demyelination loci during the pathogenesis of MS, suggesting that CYP46A1 might play a role in MS demyelination. Besides, we found that CYP46A1 was induced in LPS-stimulated microglia cell line BV-2, while CYP46A1 knockdown might attenuated LPS-induced oxidative stress via Nrf2 activation. Therefore, we suggested that CYP46A1 might contribute to MS through inhibiting Nrf2/ARE, which leads to microglia activation. We will use techniques including adeno-associated virus expression, shRNA interference, PET/CT, immunofluorescence and co-immunoprecipitation and MS models such as primary microglia model and experimental autoimmune encephalomyelitis (EAE) model to elucidate the effect of CYP46A1 in MS. Our study might help to develop a novel therapeutic target for MS.