本文選題：Mst1　切入點(diǎn)：胸腺遷出　出處：《復(fù)旦大學(xué)》2010年博士論文

【摘要】： 在細(xì)胞水平,絲氨酸/蘇氨酸激酶Mst1被證明在調(diào)控細(xì)胞凋亡、淋巴細(xì)胞極化和吸附等過程中起重要作用。但是至今還不清楚Mst1在哺乳動(dòng)物中的生理功能和作用。我們利用基因打靶技術(shù)建立了Mst1基因剔除小鼠來研究Mstl在胸腺細(xì)胞發(fā)育和遷徙中的作用。我們發(fā)現(xiàn)Mst1基因剔除會(huì)導(dǎo)致成熟T細(xì)胞在胸腺中累積、外周淋巴細(xì)胞減少以及淋巴細(xì)胞歸巢缺陷。Mstl-/-胸腺細(xì)胞對(duì)多個(gè)趨化因子,比如CCL19等,趨化性減弱,但對(duì)S1P(sphingosine-1-phosphate)趨化性沒有降低。進(jìn)一步研究發(fā)現(xiàn)Mst1-/-小鼠的胸腺細(xì)胞由于從胸腺遷出缺陷而導(dǎo)致胸腺細(xì)胞累積和外周淋巴細(xì)胞減少。T細(xì)胞特異性剔除Mst1小鼠也出現(xiàn)胸腺細(xì)胞遷出問題。 我們還發(fā)現(xiàn)Mstl-/-小鼠隨著年齡的增長(zhǎng)會(huì)漸進(jìn)性的出現(xiàn)自身免疫病癥狀,包括外淚腺和頜下腺具有淋巴細(xì)胞浸潤(rùn)區(qū)、血清中出現(xiàn)自身免疫性的ANA抗體。T細(xì)胞特異性剔除Mstl的小鼠也出現(xiàn)免疫病癥狀,說明T細(xì)胞在Mstl-/-小鼠免疫病發(fā)病中起重要作用。進(jìn)一步研究發(fā)現(xiàn)Mst1-/-小鼠胸腺中負(fù)選擇缺陷,表明中樞免疫耐受缺陷可能是Mst1-/-小鼠發(fā)生自身免疫病的原因之一。 我們的研究證實(shí)Mstl在調(diào)控淋巴細(xì)胞趨化和胸腺細(xì)胞遷出中起重要作用。此外,我們的研究首次建立了Mstl與復(fù)雜性自身免疫病之間的聯(lián)系。這為進(jìn)一步研究自身免疫病的發(fā)生機(jī)制創(chuàng)建了一個(gè)良好的動(dòng)物模型,并可能為以后的新藥開發(fā)、臨床預(yù)防、診斷和治療提供幫助。
[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.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2010
【分類號(hào)】：R392

【共引文獻(xiàn)】

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本文編號(hào)：1707979