Mst1调控胸腺细胞迁出和在中枢免疫耐受中的功能研究

发布时间：2018-04-04 02:31

本文选题：Mst1　切入点：胸腺迁出　出处：《复旦大学》2010年博士论文

【摘要】： 在细胞水平,丝氨酸/苏氨酸激酶Mst1被证明在调控细胞凋亡、淋巴细胞极化和吸附等过程中起重要作用。但是至今还不清楚Mst1在哺乳动物中的生理功能和作用。我们利用基因打靶技术建立了Mst1基因剔除小鼠来研究Mstl在胸腺细胞发育和迁徙中的作用。我们发现Mst1基因剔除会导致成熟T细胞在胸腺中累积、外周淋巴细胞减少以及淋巴细胞归巢缺陷。Mstl-/-胸腺细胞对多个趋化因子,比如CCL19等,趋化性减弱,但对S1P(sphingosine-1-phosphate)趋化性没有降低。进一步研究发现Mst1-/-小鼠的胸腺细胞由于从胸腺迁出缺陷而导致胸腺细胞累积和外周淋巴细胞减少。T细胞特异性剔除Mst1小鼠也出现胸腺细胞迁出问题。我们还发现Mstl-/-小鼠随着年龄的增长会渐进性的出现自身免疫病症状,包括外泪腺和颌下腺具有淋巴细胞浸润区、血清中出现自身免疫性的ANA抗体。T细胞特异性剔除Mstl的小鼠也出现免疫病症状,说明T细胞在Mstl-/-小鼠免疫病发病中起重要作用。进一步研究发现Mst1-/-小鼠胸腺中负选择缺陷,表明中枢免疫耐受缺陷可能是Mst1-/-小鼠发生自身免疫病的原因之一。我们的研究证实Mstl在调控淋巴细胞趋化和胸腺细胞迁出中起重要作用。此外,我们的研究首次建立了Mstl与复杂性自身免疫病之间的联系。这为进一步研究自身免疫病的发生机制创建了一个良好的动物模型,并可能为以后的新药开发、临床预防、诊断和治疗提供帮助。
[Abstract]:At the cellular level, serine / threonine kinase Mst1 has been shown to play an important role in the regulation of apoptosis, lymphocyte polarization and adsorption.However, the physiological function and role of Mst1 in mammals is unclear.We established Mst1 gene knockout mice using gene targeting technique to study the role of Mstl in thymocyte development and migration.We found that Mst1 gene knockout resulted in the accumulation of mature T cells in the thymus, peripheral lymphocytopenia and lymphocyte homing defect. Mstl-r-thymocytes became less chemotactic to multiple chemokines, such as CCL19, but not to S1Psphingosine-1-phosphate.Further studies showed that the thymocyte accumulation in Mst1-r-mouse thymocytes and peripheral lymphocytopenia. T cell specific knockout Mst1 mice also had the problem of thymocyte migration due to the defect of migration from the thymus.We also found that Mstl-r-mice developed progressive autoimmune symptoms with age, including the presence of lymphocytic infiltrating areas in the external lacrimal and submandibular glands.The presence of autoimmune ANA antibody. T cell specific Mstl knockout mice also showed signs of immune disease, indicating that T cells play an important role in the pathogenesis of Mstl-r-mice immune disease.Further studies revealed negative selection defects in the thymus of Mst1-r-mice, suggesting that central immune tolerance deficiency may be one of the causes of autoimmune disease in Mst1-r-mices.Our studies confirm that Mstl plays an important role in regulating lymphocyte chemotaxis and thymocyte migration.In addition, our study established for the first time a link between Mstl and complex autoimmune diseases.This provides a good animal model for further study of the pathogenesis of autoimmune diseases and may be helpful for the development of new drugs, clinical prevention, diagnosis and treatment in the future.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R392

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