發(fā)布時(shí)間：2018-02-04 12:38

  本文關(guān)鍵詞： 丙型肝炎病毒 核心蛋白 蛋白激酶R 信號(hào)轉(zhuǎn)導(dǎo)及轉(zhuǎn)錄激活子3 丙型肝炎病毒 核心蛋白 凋亡 基因芯片 基因表達(dá)譜　出處：《浙江大學(xué)》2005年博士論文　論文類(lèi)型：學(xué)位論文

【摘要】：丙型肝炎病毒(HCV)核心蛋白(CORE)是構(gòu)成病毒的核殼蛋白,在HCV持續(xù)感染及肝癌(HCC)的發(fā)病機(jī)制中起重要作用。不同基因型HCV編碼CORE結(jié)構(gòu)和功能存在一定的差異,且同一病毒株編碼的不同功能區(qū)域的功能不同。我國(guó)HCV感染主要流行株基因型為基因1b型。因此,研究基因1b型CORE及其不同截短片段在HCV持續(xù)感染及肝癌發(fā)病機(jī)制中的作用,對(duì)防治我國(guó)丙型肝炎具有重要的實(shí)際意義。蛋白激酶R(PKR)是干擾素(IFN)發(fā)揮抗病毒主要工具,在抵抗HCV的持續(xù)感染及HCC的發(fā)病機(jī)制中起重要作用,近年來(lái)受到特別的重視。信號(hào)轉(zhuǎn)導(dǎo)及轉(zhuǎn)錄激活子(STAT)家族在介導(dǎo)細(xì)胞信號(hào)傳導(dǎo)中起關(guān)鍵作用,其中STAT3被認(rèn)為是癌性轉(zhuǎn)錄因子,可以介導(dǎo)多種不同的生理和病理過(guò)程,包括細(xì)胞生長(zhǎng),分化凋亡,胚胎的發(fā)育,轉(zhuǎn)化,炎癥和免疫反應(yīng)。 基于對(duì)CORE研究發(fā)現(xiàn)來(lái)自HCC癌組織中HCV的CORE能與PKR發(fā)生直接作用,CORE能激活STAT3而誘發(fā)肝細(xì)胞的惡性轉(zhuǎn)化,PKR又可作為接頭蛋白。本課題進(jìn)一步對(duì)CORE與PKR、STAT3相互作用進(jìn)行了研究,并對(duì)相互作用所依賴的功能區(qū)域進(jìn)行了定位,提出了三者相互作用的模式,探討三者在HCV致病機(jī)制,為抗HCV治療提供新的靶位。 目的 (1) 探討基因1b型HCV不同截短片段CORE在HCV致病機(jī)制中的作用; (2) HCV病毒蛋白或CORE對(duì)PKR及STAT3表達(dá)水平的影響; (3) CORE與PKR及STAT3的相互作用在HCV致病機(jī)制中的作用,定位相互作用所依賴的各自功能區(qū)域; (4) 建立CORE與PKR及STAT3相互作用可能模式。 方法 (1) 構(gòu)建7個(gè)基因1b型HCV不同截短片段的谷胱苷肽S轉(zhuǎn)移酶(GST)CORE融合蛋白的原核表達(dá)質(zhì)粒pGEX 4T-1/CORE。表達(dá)純化獲得不同截短片段的GST-CORE及
[Abstract]:Hepatitis C virus (HCV) core protein (Corel) is the core-shell protein that makes up the virus. It plays an important role in the pathogenesis of HCV persistent infection and hepatocellular carcinoma (HCC). The structure and function of CORE encoded by different genotypes of HCV are different. Different functional regions of the same virus strain encode different functions. The main genotype of HCV infection in China is genotype 1b. To study the role of 1b type CORE and its different truncated fragments in the pathogenesis of HCV persistent infection and hepatocellular carcinoma. Protein kinase protein kinase (PKR) is the main antiviral tool of interferon interferon (IFN). It plays an important role in resisting the persistent infection of HCV and the pathogenesis of HCC. In recent years, special attention has been paid to the family of signal transduction and activator of transcription (STAT), which plays a key role in mediating cell signal transduction. Among them, STAT3 is considered to be a cancerous transcription factor. It mediates a variety of physiological and pathological processes, including cell growth, differentiation and apoptosis, embryonic development, transformation, inflammation and immune response. Based on the study of CORE, it was found that CORE from HCC carcinomas can directly interact with PKR. Core can activate STAT3 and induce malignant transformation of hepatocytes. PKR can also be used as a joint protein. In this study, the interaction between CORE and PKR- STAT3 was further studied, and the functional regions dependent on the interaction were located. A model of interaction among the three was proposed to explore the pathogenesis of HCV and to provide a new target for anti-HCV therapy. Purpose 1) to explore the role of different truncated CORE fragments of 1b type HCV in the pathogenesis of HCV. (2) the effect of HCV virus protein or CORE on the expression of PKR and STAT3; (3) the interaction of CORE with PKR and STAT3 in the pathogenesis of HCV, and the location of the respective functional regions on which the interaction depends; (4) to establish a possible model for the interaction of CORE with PKR and STAT3. Method Construction of glutathione S-transferase (GST) with different truncated fragments of 1b type HCV. The prokaryotic expression plasmid pGEX 4T-1 / Core of CORE fusion protein was expressed and purified to obtain different truncated GST-CORE and
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2005
【分類(lèi)號(hào)】：R373

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本文編號(hào)：1490230