蛋氨酸亚砜还原酶A负性调控氧化应激及小胶质细胞炎性激活在实验性自身免疫性脑脊髓炎中的作用及其机制

项目名称： 蛋氨酸亚砜还原酶A负性调控氧化应激及小胶质细胞炎性激活在实验性自身免疫性脑脊髓炎中的作用及其机制

项目编号： No.U1504808

项目类型： 联合基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 范华

作者单位： 河南科技大学

项目金额： 27万元

中文摘要： 多发性硬化（MS）是一种发生于中枢神经系统的自身免疫性疾病。实验性自身免疫性脑脊髓炎（EAE）由于与MS具有相似的病理特征及临床表现，已被国际公认为是MS相关研究的理想动物模型。CD4+ T细胞所介导的自身免疫反应在EAE/MS的病理进程中处于核心地位，而过度激活的小胶质细胞和氧自由基（ROS）已被证实可通过多种途径参与调控CD4+ T细胞的异常活化。因此，减缓氧化应激、抑制小胶质细胞炎性活化已成为新型MS治疗药物开发的重要研究方向。蛋氨酸亚砜还原酶A（MsrA）是体内调控蛋氨酸抗氧化防御体系的关键酶，其在EAE/MS中所扮演的角色尚不清楚。申请者在最新发表的研究成果中已证实：MsrA可直接清除ROS并进而抑制小胶质细胞所介导的神经炎症，因此，本项目旨在进一步探索MsrA在EAE/MS中的作用，并试图从小胶质细胞炎性激活及氧化应激等角度阐明机制，为以MsrA为靶点开发相关新药提供实验依据。

中文关键词： 蛋氨酸亚砜还原酶A；实验性自身免疫性脑脊髓炎；多发性硬化；氧化应激；小胶质细胞炎性激活

英文摘要： Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and experimental autoimmune encephalomyelitis (EAE) has been widely recognized as an ideal animal model of MS due to their similar pathological features and clinical manifestations. CD4+ T cell-mediated autoimmune response plays a central role in the pathological process of EAE/MS. Meanwhile, overactivated microglia and reactive oxygen species (ROS) can be directly or indirectly involved in regulating the activation, proliferation and differentiation of pathologic CD4+ T cell by many means, thereby aggravating the severity of EAE/MS. Therefore, inhibition of microglial overactivation and antioxidant therapy have become promising research directions for the treatment of MS. Methionine residues on proteins serve as a pivotal antioxidant defense that protects proteins against oxidative stress, nonetheless, their role in EAE/MS remains virtually unknown. As a key enzyme controlling the cyclic oxidation/reduction of methionine, MsrA has been confirmed to scavenge ROS and alleviate microglia-mediated neuroinflammation. Therefore, the aim of this term is to further explore the role of MsrA-catalytic methionine antioxidant defense in EAE/MS and its mechanisms. Our findings may supply experimental data for the development of novel drugs to treat MS and other autoimmune diseases.

英文关键词： methionine sulfoxide reductase A;experimental autoimmune encephalomyelitis;multiple sclerosis;oxidative stress;inflammatory activation of microglia