ZEB1通过调控CD4+T细胞表型在多发性硬化症中发病机制的研究

Recent studies have shown that ZEB1 involved in the process of invasion and metastasis of malignant tumor. ZEB1 may also regulate immune responses within the human beings. However, the regulatory effect of ZEB1 on the effector cells' function in Multiple Sclerosis have not been reported in previous literatures. Previous results showed that ZEB1 gene was upregulated in peripheral blood mononuclear cells (PBMCs) from MS patients than that from healthy controls. The results also indicated that ZEB1 gene was predominately expressed in CD4+T cells, and upregulated after activation. The clinical manifestation and pathologic characteristics of EAE mice were significantly alleviated in ZEB1 conditional knockout mice. Based on those results, we would like toinvestigate the effects of ZEB1 over-expression on the pathology of CNS autoimmune diseases using EAE mice. And we would also study the effects of ZEB1 on CD4+T cell differentiation, function, and the cytokines and chemokines expression. To explore the potential molecular mechanism underlying the regulatory effect of ZEB1 on CD4+T cells and related immune regulatory pathway, gene chip and Ingenuity Pathway Analysis platform will be involved in this study. This project will lay the theoretical foundation for the in-depth understanding of the pathogenesis of CNS autoimmune disease, and may provide new target for the treatment of MS.

近年来许多研究表明，ZEB1不仅参与了恶性肿瘤的侵袭和转移过程，对免疫应答也具有重要的调控作用，然而ZEB1在CNS自身免疫性疾病中的作用及相关机制尚不明确。我们的前期实验证实，与健康对照相比，MS患者外周血单个核细胞中ZEB1在基因和蛋白表达水平上均上调，特别是在激活的CD4+T细胞中呈优势表达。在进一步的研究中我们发现，与野生型C57BL/6小鼠相比，条件敲除ZEB1明显改善了EAE小鼠的临床评分。基于以上实验结果，本课题拟解决以下科学问题：1）阐明ZEB1对EAE模型临床表现及CNS免疫微环境的影响；2）ZEB1对CD4+T细胞激活、增殖和分化的影响；3）利用基因芯片技术及Ingenuity Pathway Analysis平台初步探索ZEB1对调控CD4+T细胞信号传到通路及相关机制。为深入理解MS的发病机制奠定基础，也为进一步开发新的治疗策略提供潜在的靶点。

ZEB1不仅参与了恶性肿瘤的侵袭和转移过程，对免疫应答也具有重要的调控作用，然而ZEB1在CNS自身免疫性疾病中的作用及相关机制尚不明确。我们的前期实验证实，与健康对照相比，MS患者外周血单个核细胞中ZEB1在基因和蛋白表达水平上均上调，特别是在激活的CD4+T细胞中呈优势表达。在进一步的研究中我们发现，与野生型C57BL/6小鼠相比，条件敲除ZEB1显著延迟EAE的发病时间，明显改善了EAE小鼠的临床评分以及症状出现的时间。基于以上实验结果，本课题解决以下科学问题：1）阐明ZEB1对EAE模型临床表现及CNS免疫微环境的影响；2）ZEB1对CD4+T细胞激活、增殖和分化的影响；3）初步探索ZEB1对调控CD4+T细胞信号传到通路及相关机制。为深入理解MS的发病机制奠定基础，也为进一步开发新的治疗策略提供潜在的靶点。