多发性硬化症(MS)是由自身免疫引发的慢性神经退行性疾病，常用的免疫类药物副作用强，缺乏神经保护和修复作用，不能根本治愈。. 前期研究发现黄芪皂苷显著降低MS动物模型EAE小鼠发病，其作用与特异性激活神经细胞转录因子EGR1密切相关；而EGR1 KO鼠病症加重，提示EGR1激活有助于EAE治疗。据此，我们提出“黄芪皂苷通过靶向激活神经元细胞EGR1，促进BDNF/TGFβ1等神经营养因子合成，减少神经元细胞损伤是其防治MS的关键机制”假说。. 本项目拟运用神经元特异性EGR1敲除、过表达和报告基因等技术，在分子、细胞、组织、动物层面，探讨EGR1/BDNF/TGFβ1通路对黄芪皂苷抗EAE疾病进程的影响，研究黄芪皂苷调控EGR1基因转录、蛋白转运、下游信号转导的作用，揭示其神经保护分子机制，为其临床防治MS奠定分子理论依据，同时为黄芪的传统中医临床应用提供现代理论基础。

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease caused by unknown reasons. More than 3 million people over the world are sufferred from the disease. Current therapies for the disease are focused on immunoregulant or immunosuppresant, which mainly modulate Th1/Th17/Treg cell differentiation or prevent the infiltration of T cells into CNS. However, there's no interventions currently that can prevent the disease thoroughly from relapsing and repair the insulted neronal network..Radix Astragali has been used in China as a tonic medicine over thousands of years. Clinical applications of compound prescriptions that contain radix astragali have been shown to significantly improve clinical symptoms of tremendous neurodegenerative diseases, such as ischemic cerebrovascular disease and spinal cord injury. Astragalosides, the major bioactive compounds found in Astragalus, have been shown to increase survival rate and enhance plasicities of many neuronal cells in enormous models. Moreover, astragalosides can regulate the differentiation of T helper cells including Th1, Th2 and Treg subtypes.Our preliminary experimental data showed that astragalosides can alleviate the clinical symptoms of mice induced with experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. Further studies displayed that astragalosides increase SOD, GSH-Px but downregulate iNOS and MDA content in the CNS of model animals. In addition, the drug treated mice expressed less apoptotic proteins such as caspase-3, Bax and p53 but enhanced Bcl-2, the anti-apoptotic protein. As a result, the phosphorylated tau proteins indicated the extent of neuronal insults were reduced in the drug treated groups. Our novel findings showed astragaloside IV significantly enhanced neuronal EGR1 at both mRNA and protein levels in vitro and in vivo, which indicated important role of EGR1 in the ASI's function. Further studies disclosed that EGR1 deletion caused the aggravation of EAE progression in mice, which also abrogated the allevative effect of ASI on the disease. In SH-SY5Y cells, EGR1 was proven to modulate the expression of BDNF and TGFβ1, the neurotrophic factors in CNS. All of these results indicated important role of EGR1 in EAE progression suggesting EGR1 as a mediator protein for the alleviative effect of astragalosides on EAE. But currently, the exact molecular basis for EGR1 in the progression of the disease has not been elucidated yet..The present proposal is aimed to elucidate the role of EGR1 in the progression of EAE by induction the disease in neuronal EGR1 knockout or overexpression mice. Moreover, the regulatory mechanisms of astragalosides on the function of EGR1 will be addressed, including the signaling pathways involved. Upon the completion of this proposal, we hope to identify EGR1/BDNF/TGFβ1 as a novel target for MS therapy and provide a detailed explanation for the preventive effect of astragalosides on EAE progression, which may pave the road for the application of astragalosides for the therapy or intervention of MS.