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系統識別號 U0026-0812200912043253
論文名稱(中文) C型肝炎病毒NS2蛋白對CD9與CD81之調控
論文名稱(英文) Regulation of CD9 and CD81 by the NS2 Protein of Hepatitis C Virus
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 94
學期 2
出版年 95
研究生(中文) 陳靜如
研究生(英文) Ching-Ju Chen
電子信箱 t3693405@mail.ncku.edu.tw
學號 t3693405
學位類別 碩士
語文別 中文
論文頁數 123頁
口試委員 指導教授-楊孔嘉
口試委員-黃暉升
口試委員-張定宗
口試委員-鄭如茜
中文關鍵字 C型肝炎病毒  NS2蛋白  CD9  CD81 
英文關鍵字 CD81  CD9  NS2 protein  HCV 
學科別分類
中文摘要 C型肝炎病毒 (Hepatitis C virus, HCV) 是一個正股RNA病毒,屬於黃熱病毒科 (Flaviviridae),HCV感染會導致嚴重的肝臟疾病包含急性和慢性的肝炎、肝硬化和肝癌。HCV基因可以製造一條大約3000個胺基酸的蛋白,再切割為10個成熟的蛋白。其中HCV非結構蛋白2 (non-structural protein 2,NS2),在HCV生活史及致病機轉中角色上尚未確定。我們曾利用微晶片 (microarray) 篩選肝癌細胞中基因表現的差異,主要發現NS2會調升CD9 mRNA的表現。CD9和HCV受體之ㄧ的CD81皆屬於四穿膜蛋白超級家族 (tetraspanin superfamily) 之一員,與細胞移行 (cell mobility)、細胞生長 (cell growth)、貼附 (adherence)、癌症生成 (carcinogenesis) 以及微生物感染 (microbial infections) 有關。在本篇的研究中,主要目標要釐清NS2調升tetraspanin蛋白之調控路徑與功能。第一,我們利用螢光標定NS2蛋白可見其表達位於被轉染Huh7細胞 (transfected cell) 的細胞質中,並且不同基因型之NS2皆會增加CD9和CD81的表現。第二,我們研究調升CD9和CD81的訊息調控因子。HCV NS2會在短時間快速地促進細胞產生氧化壓力 (oxidative stress),但這與tetraspanin的調升是無關的。然而,NS2抑制PKC-δ由細胞質轉位 (translocation) 至細胞膜,與tetraspanin之調升有關。另外,NS2會抑制ERK之磷酸化。第三,我們利用小兒麻痺病毒 (poliovirus) 和登革病毒 (dengue virus) 分析NS2調升tetraspanin的細胞對病毒之易受性,由結果顯示NS2表現會促進病毒的感染。由本篇研究推知,HCV NS2蛋白會藉由抑制PKC-δ,調升細胞表面的tetraspanin之CD9和CD81表現,進而促進細胞對於病毒的感染性。


英文摘要   Hepatitis C virus (HCV), a positive-stranded RNA virus in the Flaviviridae family, can cause various liver diseases including acute and chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV genome encodes a polyprotein of about 3,000 amino acids, which are processed into 10 mature viral proteins. Among these, the functions of non-structural protein 2 (NS2) are largely unknown in the HCV life cycle and pathogenesis. Our previous studies with microarray technology resulted in up-regulation of CD9 mRNA expression by the HCV NS2. As we know CD9 and CD81, a putative HCV receptor, belong to tetraspanin superfamily, in which the members are considered to be related to cell mobility, cell growth, adherence, carcinogenesis, and microbial infections. In this study, we aimed to characterize the regulatory pathways and biological relevance of the NS2-mediated tetraspanin up-regulation. First, the results showed that the fluorescence-tag NS2 proteins were localized in the cytoplasm of transfected Huh7 cells and that the HCV NS2 proteins of various genotypes could increase surface CD9 and CD81 expression. Next, we identified the signally mediators in regulation of CD9 and CD81. A rapid and short induction of oxidative stress was detected, but not correlated with tetraspanin modulation. However, suppression of PKC-δ translocation from cytosol to membrane conferred the NS2 modulation of tetraspanin up-regulation. In additional, ERK phosphorylation was also decreased in NS2 expressing cells. Third, we analyzed the effects of NS2-mediated tetraspanin up-regulation on cell susceptibility to poliovirus and dengue virus, with the results showing the NS2 proteins might promote the virus infection. In conclusion, the HCV NS2 protein can upregulate the surface expressions of tetraspanin CD9 and CD81, which is mediated by inhibition of PKC-δ, and facilitate the infection of susceptible viruses.


論文目次 中文摘要--I
英文摘要--Ⅱ
誌謝 (Acknowledgements)--Ⅲ
目錄 (Index)--Ⅳ
圖/表/附錄 (Figures/Table/Appendixes)--Ⅷ
藥品與儀器 (Reagents and Instruments)--Ⅹ
壹、緒論 (Introduction)--1
一、C型肝炎病毒 (Hepatitis C Virus,HCV)--2
1. C型肝炎之流行病學 (Epidemiology of HCV)--2
2. C型肝炎病毒蛋白之結構與功能 (The Structure and Function of HCV)--5
3. C型肝炎病毒之複製與生活史 (HCV Replication and Life Cycle)--8
二、C型肝炎病毒非結構蛋白2 (HCV NS2 Protein)--10
三、四穿膜蛋白家族 (Tetraspanin Superfamily)--11
1. 四穿膜蛋白的構造與功能 (The Structure and Function of Tetraspanin)--11
2. CD9蛋白 (CD9 Protein)--12
3. CD81蛋白 (CD81 Protein)--13
四、慢性病毒感染與內質網壓力 (Chronic Virus Infection and Endoplasmic Reticulum Stress)--14
五、蛋白質激酶C (Protein Kinase C,PKC)--15
六、細胞外調節激酶 (Extracellular-regulated kinase,ERK)--18
七、研究目摽 (Study Aims)--18
貳、實驗材料與方法 (Materials and Methods)--21
一、細胞培養--22
二、萃取HCV RNA與HCV RT-PCR--24
三、以InnoLipa strip定出HCV基因型--26
四、構築標準質體--28
五、細胞瞬間轉染DNA和SiRNA--34
六、建立穩定的轉染細胞株--35
七、流式細胞儀偵測CD9、CD81及ROS--39
八、備置細胞蛋白質與分離細胞之細胞質和細胞膜--40
九、西方墨點法分析PKC和ERK蛋白質--42
十、病毒斑試驗--45
參、實驗結果 (Results)--48
一、分析表現HCV NS2之肝癌細胞中的CD9和CD81之表現量--50
1. 利用流式細胞儀分析CD9 和CD81蛋白表現--50
a. 相關NS2片段之質體--50
b. NS2主要存在細胞質--51
c. NS2瞬間轉染20小時和48小時之CD9和CD81表現--51
d. 建立穩定表現NS2轉染細胞株--52
二、分析並比較HCV病人血清的NS2之序列--53
1. 利用Inno-LiPA分析HCV基因型--53
2. 構築不同基因型NS2之標準質體--54
3. 序列分析與比對--54
4. 不同基因型之NS2所調控的CD9和CD81之差異--54
三、探討HCV NS2促進CD9和CD8蛋白上升之調控路徑------55
1. 探討NS2調控CD9和CD81與ROS pathway之關係--55
2. 探討NS2調控CD9和CD81與PKC之關係--56
a. PKC活化劑和抑制劑篩選PKC與CD9和CD81之相關性-----57
b. 西方墨點法偵測PKC isoform--58
c. 以PKC SiRNA證實PKC isoform與CD9和CD81之關係-----59
3. 分析NS2與ERK pathway之關係--60
四、HCV NS2蛋白之功能性探討--61
1. 病毒斑試驗--61
2. 感染性中心分析試驗--62
肆、討論 (Discussion)--63
一、HCV與HCV NS2蛋白--64
二、分析表現HCV NS2之肝癌細胞中的CD9和CD81之表現---65
三、分析並比較HCV病人血清的NS2之序列--67
四、HCV NS2促進CD9和CD8蛋白上升之調控路徑--67
五、HCV NS2蛋白之功能性探討--69
伍、結論 (Conclusion)--71
陸、參考文獻 (References)--72
柒、圖/表 (Figures/Tables)--79
捌、附錄 (Appendix)--113
玖、作者 (Author)--123
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