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研究生:陳怡君
研究生(外文):Yi-Jiun Chen
論文名稱:探討D型肝炎病毒抗原蛋白之標地基因
論文名稱(外文):Identification of Hepatitis Delta Antigens Target Genes
指導教授:吳妍華
指導教授(外文):Yan-Hwa Wu Lee
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生物化學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:88
中文關鍵詞:D型肝炎病毒大型D型肝炎病毒抗原蛋白小型D型肝炎病毒抗原蛋白
外文關鍵詞:HDVchromatin immunoprecipitationAffymetrix GeneChipLHDAgSHDAg
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D型肝炎病毒(Hepatitis delta virus;HDV)為一個直徑36 nm的病毒顆粒,含有B型肝炎病毒的表面抗原作為其套膜及一條單股、環狀、1.7 kb長的RNA基因體,以及大、小型D型肝炎病毒抗原蛋白。已知大型的D型肝炎病毒抗原蛋白對D型肝炎病毒顆粒的組成是必須的;而小型的D型肝炎病毒抗原蛋白功能則為幫助D型肝炎病毒的複製。先前的研究中發現D型肝炎病毒抗原蛋白對於宿主細胞可能具有毒殺性,且D型肝炎病毒抗原蛋白與Bax蛋白及c-Myc蛋白有極高的相關性;此外,D型肝炎病毒抗原蛋白具有調控啟動子及包含轉錄因子結合區域之報導質體的活性。本論文旨在探討大、小型D型肝炎病毒抗原蛋白會調控哪些細胞內基因的表現,進而說明D型肝炎病毒可能的致病機轉。我們採用chromatin immunoprecipitation clonig的方法探討與大型D型肝炎病毒抗原蛋白結合的DNA序列。此外,我們亦利用Affymetrix GeneChip expression analysis分析在D型肝炎病毒抗原蛋白持續表現下,宿主細胞哪些基因表現受到影響。實驗結果發現大型D型肝炎病毒抗原蛋白可能會藉由坐落在基因之遠端區域上調控目標基因之表現量。大型D型肝炎病毒抗原蛋白會與一些和調控metabolism、cell proliferation、transcription regulation、tumor suppressor、cell motility、neurogenesis、RNA splicing、signal transduction、cell adhesion及protein trafficking相關的基因結合。其中已確定HTATIP基因及UNC5C 基因之DNA序列會與大型D型肝炎病毒抗原蛋白有交互作用,而小型D型肝炎病毒抗原蛋白會與HTATIP基因之DNA序列有交互作用,而在luciferase assay的結果中發現大型D型肝炎病毒抗原蛋白對UNC5C基因的intron 1區域的轉錄活性具有活化的效果,卻對HTATIP基因之3’非轉錄區域的轉錄活性沒有明顯之影響;而小型D型肝炎病毒抗原蛋白對HTATIP基因之3’非轉錄區域及UNC5C基因的intron 1區域的轉錄活性沒有明顯影響。而Affymetrix Genechip expression analysis的實驗結果顯示在有D型肝炎病毒抗原蛋白持續表現的情形下,發現其中大部分受到影響的基因是與metabolism、development、signal transduction、transport、cell growth regulation、transcription regulation、cell cycle regulation及immune response方面有相關,暗示D型肝炎病毒抗原蛋白有可能藉由影響宿主細胞的正常代謝,或藉由影響其他基因表現,因而造成其致病之原因。
Hepatitis delta virus (HDV) infection may lead to fulminant acute hepatitis or severe chronic hepatitis, which often progress to cirrhosis. HDV is a single-stranded RNA virus that encodes two viral nucleocapsid proteins designated small and large form of hepatitis delta antigen (SHDAg and LHDAg). These two proteins are identical in sequence except that the large form contains an additional 19 amino acids at its C terminus. The SHDAg is essential for viral RNA replication while the LHDAg is required for viral assembly. Previous studies have revealed that LHDAg and SHDAg regulate several promoters and transcription factor containing reporters. SHDAg possesses a cytotoxic effect on infected hepatocytes. In this study, we employed chromatin immunoprecipitation cloning method to identify HDAg target genes. We found that LHDAg interacts with several genes that involved in metabolism, cell proliferation, transcription regulation, tumor suppressor, cell motility, neurogenesis, RNA splicing, signal transduction, cell adhesion and protein trafficking. We also found that both LHDAg and SHDAg interact with HTATIP gene, which is a histone acetyltranferase and is involved in double-stranded DNA break repair and apoptotic competence. Moreover, only LHDAg but not SHDAg interacts with UNC5C, which is considered as a putative tumor suppressor gene. LHDAg activates the transcription activity of the intron 1 region of UNC5C gene containing reporter, but has no effect on the transcription activity of 3’ UTR of HTATIP gene containing reporter. SHDAg seems to have no effect on the transcription activity of both the the intron 1 region of UNC5C gene and 3’ UTR of HTATIP gene containing reporters. Furthermore, using Affymetrix GeneChip expression analysis, results indicate that several cellular genes are regulated under HDAgs overexpressing, especially the genes involved in metabolism, development, signal transduction, transport, cell growth regulation, transcription regulation, cell cycle regulation and immune response. These results may provide clues that will aid in the understanding of the pathogenesis mechanism of HDV.
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