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研究生:鄭家弘
研究生(外文):Chia-Hung Cheng
論文名稱:腸病毒71型內部核醣體進入區之功能性分析:研究其分子基礎與神經毒性
論文名稱(外文):Functional Analysis of the Internal Ribosomal Entry Site of Enterovirus 71: Investigation into Molecular Basis of the Neurovirulence
指導教授:龔思豪
指導教授(外文):Szu-Hao Kung
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:醫學生物技術暨檢驗學系暨研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:109
中文關鍵詞:腸病毒71型內部核醣體進入區神經趨性
外文關鍵詞:EV71IRESITAFUnrneurotropismEnterovirus 71
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  腸病毒71型屬於小RNA病毒,在台灣從1998年至今已經造成數次大流行,會引起嚴重的神經症狀。病毒5’未轉譯區中的internal ribosomal entry site(IRES)二次結構會與核醣體結合,進行病毒蛋白質的轉譯起始,與致病能力相關,但是與神經趨性是否相關仍然存有爭議。另一方面,病毒IRES與核醣體的結合需要細胞中IRES trans-acting factors(ITAFs)的參與,而目前對腸病毒71型ITAF的了解仍然有限。
  在此篇研究中,我們使用EMCV、腸病毒71型BrCr標準株、腸病毒71型B5台灣臨床株、第三型小兒麻痺病毒沙賓疫苗株、第三型小兒麻痺病毒沙賓疫苗回復突變株、A群克沙奇病毒第十六型的IRES,建構出帶有螢火蟲以及水母冷光�〞甄蠽N光報導基因質體,測定其IRES活性。藉由分析在神經細胞與非神經細胞中IRES活性之差異,了解IRES與神經趨性之間的關係。結果發現雖然不同病毒其IRES活性也有所不同,但是在神經細胞與非神經細胞間卻沒有差異,表示腸病毒的IRES活性不受神經系統與否所影響,因此腸病毒的神經趨性是由IRES以外的因素所造成。
  另一方面,觀察已知的小兒麻痺病毒ITAFs:La autoantigen、PTB、PCBP2、Unr是否也會與腸病毒71型IRES作用,來找出腸病毒71型的ITAF。使用核醣核酸干擾策略抑制細胞內這些蛋白的表現,發現抑制Unr蛋白的表現,會造成腸病毒71型的IRES活性顯著下降;並且於受腸病毒71型感染的細胞中,其病毒蛋白表現量會因Unr蛋白的抑制而降低,製造的病毒顆粒也會減少。因此我們發現了Unr蛋白為腸病毒71型的重要ITAF之一。
Enterovirus 71 (EV71), a member of Picornaviridae family, can lead to severe neurological complications, and has caused several large outbreaks in Taiwan since 1998. The 5’ untranslated region (5’-UTR) of viruses is highly structured, containing the internal ribosomal entry site (IRES) that is critical for translation initiation. The efficiency of IRES-dependent translation is concerned with the infectivity of viruses, but whether the IRES is concerned with neurotropism or not is still controversial. On the other hand, the IRES-dependent translation initiation needs noncanonical factors called IRES trans-acting factors (ITAFs). Nowadays, the understanding of EV71 ITAFs is still limited.
In this study, we used a dual-luciferase reporter system that harbored IRES from EMCV, EV71 BrCr strain, EV71 B5 strain Taiwan isolate, Sabin type 3 vaccine strain, Sabin type 3 revertant strain, and CA16. By analyzing the IRES activities in neural and non-neural cells, we found that different viruses showed distinct IRES activities, yet each IRES activity is comparable in the two origins of cells. Accordingly, we suggested that the neurotropism of human enterovirus is not governed by viral IRES.
Additionally, we investigated La, PTB, PCBP2, and Unr, the known ITAFs of poliovirus, on their roles in interacting with EV71 IRES. Utilizing RNA interference strategy to knock down these proteins in HeLa cells, we showed that knock down of Unr, but not other ITAFs, could significantly decrease EV71 IRES activity. The decreased level of Unr also led to reduced viral protein expression and viral particle production. We revealed that Unr, among the ITAFs investigated, played the most significant role in controlling EV71 IRES.
中文摘要 3
Abstract 4
第一章 緒論 5
第一節 腸病毒概述 5
第二節 腸病毒71型 8
第三節 內部核醣體進入區 (Internal Ribosomal Entry Site, IRES) 10
第四節 核醣核酸干擾方法 17
第五節 研究緣由與目的 19
第二章 實驗材料與方法 20
第一節 細胞株的培養與操作 20
第二節 病毒的培養與定量 23
第三節 質體建構 26
第四節 測定腸病毒IRES於神經細胞與非神經細胞之轉譯起始能力 44
第五節 細胞內nPTB含量 47
第六節 使用siRNA抑制細胞內ITAFs表現 50
第七節 抑制ITAFs對腸病毒71型的影響 56
第三章 實驗結果 60
第一節 腸病毒IRES之轉譯起始能力 60
第二節 腸病毒IRES於神經細胞之轉譯起始能力 61
第三節 IRES與神經趨性之關係 62
第四節 腸病毒71型B5台灣臨床株 5’端未轉譯區之基因序列分析 63
第五節 抑制細胞內ITAFs對腸病毒71型之影響 64
第六節 siRNA雙重抑制對腸病毒71型之影響 66
第四章 討論 67
第一節 不同病毒IRES轉譯起始能力之差別 67
第二節 IRES與神經趨性之關係 68
第三節 腸病毒71型之ITAF 70
第五章 圖表 72
第六章 附錄 95
第七章 參考文獻 102
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