SARS-CoV核衣壳蛋白调控TGF-β信号转导的研究

发布时间：2018-05-06 06:23

本文选题：SARS相关性冠状病毒核衣壳蛋白 + 转化生长因子-β　；参考：《清华大学》2007年博士论文

【摘要】： 严重急性呼吸综合症(severe acute respiratory syndrom, SARS)是一种死亡率很高的急性传染病,它的主要临床症状是弥漫性肺泡损伤引起的呼吸窘迫,严重的会引发肺纤维化而使肺功能丧失。引起SARS的病原体是一种新型冠状病毒-SARS相关性冠状病毒(SARS-associated coronavirus, SARS-CoV)。核衣壳蛋白(nucleocapsid protein, N protein)是SARS-CoV的一个结构蛋白。研究发现,N蛋白参与病毒的组装并调控一些与病程相关的事件,如宿主细胞基因表达调控、骨架蛋白重组、细胞周期进程和凋亡。转化生长因子-β(transforming growth factor-β, TGF-β)在体内具有重要而广泛的生物学效应,影响多种生理和病理过程,如TGF-β通过促进细胞外基质沉积参与组织纤维化进程;TGF-β能够诱导多种类型正常细胞及肿瘤细胞发生凋亡。在SARS发病过程中,包括TGF-β1在内的多种促炎症因子表达升高。但TGF-β参与SARS感染引起的病理变化的具体机制现在还不是很清楚。我们的研究发现,SARS-CoV N蛋白通过和Smad3的相互作用增强人肺上皮细胞HPL1中TGF-β诱导的纤溶酶原激活因子抑制剂(plasminogen activator inhibitor-1, PAI-1)的表达,但是抑制Smad3/Smad4诱导的细胞凋亡。N蛋白增强TGF-β诱导的转录激活作用具有Smad3通路特异性。N蛋白和Smad4竞争结合Smad3,参与PAI-1转录复合物的形成,增强Smad3和p300所形成的转录复合物的稳定性。在SARS患者肺组织中,有细胞凋亡现象存在,但这些凋亡细胞与SARS-CoV感染的细胞并没有明显的共定位。N蛋白通过抑制促凋亡蛋白Bax和Bim的表达,抑制Smad3/Smad4诱导的HPL1细胞凋亡。综上所述,我们的研究发现了SARS-CoV N蛋白抑制细胞凋亡的同时,通过增加TGF-β诱导的细胞外基质的沉积,参与了SARS患者肺纤维化进程。这对于揭示SARS致病机理及针对TGF-β信号转导分子的治疗SARS药物的开发具有重要意义。
[Abstract]:Severe acute respiratory syndrome ( SARS ) is an acute infectious disease with high mortality . Its main clinical symptoms are respiratory distress caused by diffuse alveolar injury , and severe pulmonary fibrosis caused by pulmonary fibrosis . The pathogen of SARS is a new coronavirus - SARS - associated coronavirus ( SARS - CoV ) . Nucleocapsid protein ( N protein ) is a structural protein of SARS - CoV . It is found that N protein is involved in the assembly of the virus and regulates some events related to the course , such as the regulation of the expression of host cell gene , the recombination , the cell cycle progression and apoptosis .

Transforming growth factor - 尾 ( TGF - 尾 ) has an important and extensive biological effect in vivo , which affects various physiological and pathological processes , such as TGF - 尾 , which can induce apoptosis of various types of normal cells and tumor cells . TGF - 尾 can induce the expression of various types of normal cells and tumor cells . However , the specific mechanism of TGF - 尾 involved in the pathological changes caused by SARS infection is not clear .

We found that the interaction of SARS - CoV N protein and Smad3 enhanced the expression of TGF - 尾 - induced plasminogen activator inhibitor - 1 ( PAI - 1 ) in human lung epithelial cells , but inhibited Smad3 / Smad4 - induced apoptosis .

In conclusion , we have found that SARS - CoV N protein can inhibit the apoptosis of SARS patients , and participate in the process of pulmonary fibrosis in SARS patients by increasing the deposition of extracellular matrix induced by TGF - 尾 . This is of great significance to reveal the pathogenesis of SARS and the development of anti - SARS drugs for TGF - 尾 signal transduction molecules .

【学位授予单位】：清华大学
【学位级别】：博士
【学位授予年份】：2007
【分类号】：R511.9;R373

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