星形胶质细胞在中枢神经系统（CNS）自发免疫性疾病多发性硬化（MS）和其动物模型实验性自身免疫性脑脊髓炎（EAE）中发挥多种关键性的作用。通过筛选，我们发现EAE可以诱导星形胶质细胞中去泛素化酶OTUD7B的表达上调。为了深入研究这一现象，我们构建了在星形胶质细胞内特异性敲除OTUD7B的GFAP-Cre OTUD7Bfl/fl小鼠，并发现该小鼠发展出比对照组小鼠更严重的EAE；此外，敲除OTUD7B的星形胶质细胞在受到TNF刺激时产生更多的致炎性因子。这些前期结果提示OTUD7B可能通过阻碍TNF诱导的星形胶质细胞活化而抑制EAE。本课题中，我们拟利用蛋白质组学、原代星形胶质细胞培养、构建双重基因敲除小鼠以及检测OTUD7B在MS病人脑组织中的表达等技术，从分子、细胞、动物和临床多层次阐明星形胶质细胞OTUD7B在CNS自发免疫性疾病中的作用及其分子机制，为MS的治疗提供潜在的新靶点。

Astrocytes play critical roles in the central nervous system (CNS) autoimmune disease multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). In our previous study, we found that the expression of OTUD7B was upregulated in astrocytes during EAE. To study the function of astrocytic OTUD7B, we generated GFAP-Cre OTUD7Bfl/fl mice, which lacked OTUD7B specifically in astrocytes. Compared with OTUD7Bfl/fl control mice, GFAP-Cre OTUD7Bfl/fl mice developed more severe EAE. Besides, upon in vitro stimulation with TNF, OTUD7B-deficient astrocytes produced significantly more proinflammatory molecules than did OTUD7B-sufficient astrocytes. Collectively, these results indicate that astrocytic OTUD7B ameliorates EAE by inhibiting TNF-induced activation of astrocytes. In the proposed project, we will apply a wide range of techniques, such as proteomics, primary astrocyte culture, construction of double knockout mice, and detection of OTUD7B in MS brain tissue, to elucidate the function and molecular mechanism of astrocytic OTUD7B in CNS autoimmunity, thereby providing potential novel targets for the treatment of MS.