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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 高嘉宏,劉俊人,吳慧琳 | |
| dc.contributor.author | Huei-Ru Cheng | en |
| dc.contributor.author | 鄭惠如 | zh_TW |
| dc.date.accessioned | 2021-06-16T06:45:40Z | - |
| dc.date.available | 2017-10-15 | |
| dc.date.copyright | 2014-10-15 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-07-28 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57427 | - |
| dc.description.abstract | 慢性B型肝炎感染患者血清中的B型肝炎表面抗原 (hepatitis B surface antigen, HBsAg) 由陽性轉為陰性代表肝炎活性減少和良好預後，但目前我們對於各種HBV感染族群HBsAg轉為陰性的機制還不是十分清楚。血清中HBsAg轉陰包含HBsAg真正消失、病毒突變造成HBsAg抗原性改變測不到及存在隱藏性B型肝炎病毒感染 (occult hepatitis B virus infection, OHB)等狀況。本論文將從病毒及宿主的角度來探究不同成因肝炎患者與HBsAg轉陰的相關性，包括三個部分：
(1) 利用治療後或自然發生HBsAg轉陰患者探討隱藏性B型肝炎病毒感染之臨床和病毒學特徵。此研究共收集44位B型肝炎病毒表面抗原轉陰患者，包含15位B型肝炎病毒和C型肝炎病毒雙重感染於長效性干擾素 (pegylated interferon, PEG-IFN) 合併雷巴威林 (ribavirin, RBV) 治療後HBsAg轉陰患者；13位單一B型肝炎病毒感染於不同抗病毒藥物治療後HBsAg轉陰患者；16位單一B型肝炎病毒感染，未接受任何治療而HBsAg自然轉陰患者。藉由隱藏性B型肝炎病毒感染患者中病毒基因體突變來探討影響HBsAg轉陰的機制。44位患者中有15位患者為血清HBV DNA陽性，因此此族群隱藏性B型肝炎病毒感染盛行率為34.1%。6位HBV和HCV雙重感染於長效型干擾素合併雷巴威林治療的隱藏性B型肝炎病毒感染患者中， C3050T單一位點突變 (point mutation) 可能和HBsAg轉陰有關。此突變點位於preS2/S啟動子(promoter) 和與其重疊的HBV聚合酶基因上，它不會改變聚合酶的胺基酸序列，但在螢光素酶報導基因檢測 (luciferase reporter assay) 中顯著降低preS2/S啟動子的活性 (P = 0.0008)，對HBV複製、轉錄和轉譯則沒明顯影響。 (2) 接著以宿主角度探討慢性HBV患者中，兩個與人類白血球抗原相關的單一核苷酸多形性 (single nucleotide polymorphism, SNP)，分別是靠近人類白血球抗原HLA-DPA1 之rs3077 (human leukocyte antigen, HLA) 和HLA-DPB1之rs9277535，對HBsAg自然轉陰的影響。在個案對照研究中，收集100位HBeAg陰性/HBsAg自然轉陰的慢性B型肝炎感染男性患者 (個案組) 和100位年齡相符且HBeAg陰性/HBsAg陽性的慢性B型肝炎感染男性患者 (對照組)。分析不同基因型在這兩個族群的分布。結果發現，rs9277535 non-GG基因型比率在個案組較多 (57% vs. 42%)。慢性B型肝炎感染患者帶有rs9277535 non-GG基因型有較高機會造成HBsAg轉陰 (OR: 1.83, 95% CI: 1.04~3.21, P= 0.034)。相較於rs3077-rs9277535 GG基因單套型(haplotype)，GA基因單套型和HBsAg轉陰有較高之相關性 (OR: 2.17; 95% CI: 1.14~4.16, P= 0.030)。 (3) 探究不同慢性肝炎感染族群中，血清微核糖核酸-122 (microRNA-122, miR-122) 的量和臨床表徵的關係。miR-122會刺激C型肝炎病毒複製，但反之會抑制B型肝炎病毒複製。因此，在HBV和HCV雙重感染患者中，miR-122的變化和臨床表徵將是有趣且重要的議題。此研究共收集76位HBV和HCV雙重感染患者；105位單一HCV感染患者和39位單一HBV感染患者，皆使用長效型干擾素為基礎之治療。另外也收集14位非B/非C但ALT異常患者和20位健康受試者作為對照組。血清miR-122濃度以靈敏度高的新方法定量。治療前，單一HCV感染患者血清miR-122濃度低於單一HBV感染患者，當有HBV共同感染時，血清中miR-122濃度會增加。在多變項分析中，HBV和HCV雙重感染及單一HBV感染患者，血清中miR-122濃度和HBsAg成正相關。在HBV和HCV雙重感染患者中，治療前血清miR-122濃度較高者，在治療後血清HBsAg濃度下降幅度較大。 綜合此三部分的研究，吾人發現C3050T單一位點突變會降低preS2/S啟動子活性，可能和HBsAg測不到有關，然而可能有其他重要因素在隱藏性B型肝炎感染患者之HBsAg清除上扮演重要角色。而慢性HBV帶原者帶有HLA-DPBA1 rs9277535non-GG基因型較容易發生HBsAg自然轉陰。HBV和HCV雙重感染患者血清miR-122和HBsAg濃度有高度相關性。這些發現將可提供臨床上預測病毒性肝炎治療預後的指標。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2021-06-16T06:45:40Z (GMT). No. of bitstreams: 1 ntu-103-D97421002-1.pdf: 2231526 bytes, checksum: dd2bffe969d4088b45d95b5e6278b79f (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 中文摘要………………………………………………...................................……........I
英文摘要……………………………………...…..................................…………........IV 第一章 緒論……………………………….......................……………………............1 1.1 B型肝炎病毒感染和C型肝炎病毒感染是全球重要的健康議題...................1 1.2 B型肝炎病毒感染...............................................................................................2 1.2.1 B型肝炎病毒感染之分子生物學................................................................2 1.2.2 B型肝炎病毒之自然病史和治療................................................................3 1.3 C型肝炎病毒感染...............................................................................................5 1.3.1 C型肝炎病毒之結構....................................................................................5 1.3.2 C型肝炎病毒感染之自然病史和治療........................................................6 1.4 HBV和HCV雙重感染........................................................................................7 1.5 B型肝炎表面抗原消失的探討...........................................................................8 1.5.1 文獻回顧.......................................................................................................8 1.5.1.1 宿主因子 (host factor)...........................................................................8 1.5.1.1.1 人類白血球抗原(Human Leukocyte Antigen, HLA).......................9 1.5.1.1.2 微核醣核酸 (microRNA)...............................................................10 1.5.1.1.3微核醣核酸-122 (microRNA -122)..................................................10 1.5.1.2 病毒因子 (viral factor)........................................................................11 1.5.1.3 其他病毒共同感染................................................................................12 1.6 過去相關研究之限制........................................................................................12 1.7 尚未解決的問題................................................................................................13 1.8 研究問題及重要性............................................................................................14 1.9 研究假說及策略...............................................................................................15 第二章 材料及研究方法…………………………………………..………...............16 2.1 探討隱藏性B型肝炎患者經治療後HBsAg消失的機制................................17 2.1.1 病人來源和資料收集...................................................................................17 2.1.1.1 研究設計................................................................................................17 2.1.1.2 資料收集................................................................................................18 2.1.2 血清病毒學分析...........................................................................................18 2.1.2.1 病毒學標記............................................................................................18 2.1.2.2 HBV DNA和HCV RNA的萃取、定量及病毒基因型的檢測..............19 2.1.3 B型肝炎病毒全長基因序列和次基因體的增幅和定序...........................19 2.1.4 病毒野生株和變異株複製能力之比較.....................................................20 2.1.4.1 質體 (Plasmid constructions)..............................................................20 2.1.4.2 點突變(site-directed mutagenesis).......................................................21 2.1.4.3 細胞培養 (Cell culture)和細胞轉殖(Transfection)............................22 2.1.4.4 螢光素活性檢測(Luciferase assay).....................................................22 2.1.4.5 南方點墨法和北方點墨法..................................................................22 2.1.4.6 西方點墨法..........................................................................................24 2.1.5 免疫組織化學染色分析和定量.................................................................25 2.1.6 統計分析.....................................................................................................25 2.2 慢性B型肝炎帶原者之人類白血球抗體-DPA1和人類白血球抗體-DPB1分 布和B型肝炎表面抗原自然消失之相關性..............................................................26 2.2.1 研究設計和患者收集.................................................................................26 2.2.2 血清病毒學分析.........................................................................................27 2.2.2.1 病毒學檢測............................................................................................27 2.2.2.2 HBV DNA的萃取及病毒基因型的檢測...............................................27 2.2.3 Genomic DNA的萃取................................................................................27 2.2.4 單一核苷酸多型性rs3077和rs9277535分析...........................................27 2.2.5 統計分析.....................................................................................................28 2.3 慢性B型肝炎患者接受治療後，血清中miR-122和HBsAg的減少之相關 性.................................................................................................................................29 2.3.1 研究設計和資料收集.................................................................................29 2.3.2 血清學分析.................................................................................................29 2.3.3 微核醣核酸-122定量.................................................................................30 2.3.4 統計分析.....................................................................................................30 第三章 結果.................................................................................................................31 3.1 探討隱藏性B型肝炎患者經治療後HBsAg消失的機制..................................31 3.1.1 研究族群臨床和病毒學上的特色.............................................................31 3.1.2 HBV基因體序列突變點分析....................................................................32 3.1.3 C3050T單一突變點對S啟動子活性、HBV複製和表現的影響.............33 3.1.4 血清和肝細胞內HBsAg比較....................................................................34 3.2 慢性B型肝炎帶原者之人類白血球抗體-DPA1和-DPB1和B型肝炎表面抗 原自然消失有關.........................................................................................................35 3.2.1 研究族群臨床和病毒學上的特色.............................................................35 3.2.2 單一核苷酸多型性rs3077和rs9277535與HBsAg自然消失有關..........35 3.3 慢性B型肝炎患者接受治療後，血清中miR-122和HBsAg的減少有關........37 3.3.1 微核醣核酸-122濃度在不同慢性肝炎族群中的表現不同.....................37 3.3.2 影響微核醣核酸-122表現的可能因子......................................................37 3.3.3 血清中ALT、HBsAg和微核醣核酸-122濃度之相關性........................38 3.3.4 HBV和HCV雙重感染患者治療前血清中微核醣核酸-122濃度和長效 型干擾素治療反應之相關.....................................................................................38 3.3.5 長效型干擾素合併雷巴威林治療前後，HBV和HCV雙重感染患者血 清miR-122濃度的比較..........................................................................................39 第四章 討論.................................................................................................................40 第五章 展望.................................................................................................................47 5.1 基礎和臨床應用................................................................................................47 5.2 未來研究方向....................................................................................................47 5.2.1 與HBsAg消失有關的病毒因子..................................................................47 5.2.2 與HBsAg消失有關的宿主因子..................................................................48 5.2.3 釐清肝臟和血清miR-122濃度的關係........................................................48 第六章 英文簡述 (ENGLISH SUMMARY)............................................................49 INTRODUCTION.......................................................................................................49 MATERIAL AND METHODS...................................................................................51 Patient Cohort..........................................................................................................51 Serological assays....................................................................................................51 Extraction, amplification and sequencing of serum HBV DNA.............................51 Cloning of PCR products and isolation of plasmid DNA.......................................52 Cell culture and transfection....................................................................................52 Luciferase assays.....................................................................................................52 Southern and northern hybridization.......................................................................52 Western hybridization..............................................................................................53 Extraction genomic DNA........................................................................................53 Determination of single nucleotide polymorphisms of rs3077 and rs9277535......53 Quantification of serum miR-122............................................................................53 Ethical considerations..............................................................................................54 Statistical analysis....................................................................................................54 RESULTS....................................................................................................................55 DISCUSSION AND PERSPECTIVE.........................................................................60 第七章 參考文獻.........................................................................................................65 第八章 表與圖.............................................................................................................77 第九章 縮寫表...........................................................................................................111 第十章 附錄...............................................................................................................114 10.1 修業期間發表之相關文獻..............................................................................114 10.2 修業期間發表之其他文獻..............................................................................114 | |
| dc.language.iso | zh-TW | |
| dc.title | 慢性B型肝炎病毒感染者清除B型肝炎表面抗原之病毒學和宿主基因機轉探討 | zh_TW |
| dc.title | Virologic and Host Genetic Mechanisms of HBsAg Seroclearance in Patients with Chronic Hepatitis B Virus Infection | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 董馨蓮,施嘉和,黃怡翔 | |
| dc.subject.keyword | B型肝炎病毒,B型肝炎表面抗原自然轉陰,B型和C型肝炎病毒雙重感染,隱藏性B型肝炎病毒感染,單一核?酸多形性,微核糖核酸-122, | zh_TW |
| dc.subject.keyword | chronic hepatitis B,spontaneous hepatitis B surface antigen loss,HBV/HCV dual infection,occult hepatitis B virus infection,single nucleotide polymorphism,microRNA-122, | en |
| dc.relation.page | 115 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-07-28 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 臨床醫學研究所 | zh_TW |
| 顯示於系所單位： | 臨床醫學研究所 | |
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