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研究生:許育甄
研究生(外文):Yu-Chen Hsu
論文名稱:D型肝炎病毒的感染和發病機制及治療策略
論文名稱(外文):Infection and pathogenesis of hepatitis D virus and treatment strategies
指導教授:吳肇卿
指導教授(外文):Jaw-Ching Wu
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:英文
論文頁數:87
中文關鍵詞:肝癌D型肝炎病毒
外文關鍵詞:Hepatocellular carcinomaHepatitis D Virus
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摘要

D型肝炎病毒是個有缺陷的RNA病毒,他必須要有B型肝炎的病毒的幫助才能進行病毒的裝配及傳播。透過持續引發肝臟的發炎,D型肝炎病毒的感染可導致慢性肝炎,肝硬化和肝細胞癌(HCC)。雖然D型肝炎病毒的共同感染可以通過HBV疫苗預防,但到目前為止,慢性D型肝炎病毒感染仍沒有有效的治療方法。
此外,之前的研究表示,HBV複製可能被D型肝炎病毒抑制。雖然D型肝炎病毒與HBV相互作用的機制尚不清楚,但在研究D型肝炎病毒病毒學的同時應考慮與HBV的作用。
D型肝炎病毒的RNA可轉錄及轉譯兩種D型肝炎抗原,分別是大型D型肝炎抗原(L-HDAg)及小型D型肝炎抗原(S-HDAg),兩者均在調控HDV的複製中扮演重要的腳色。由先前文獻指出,小型D型肝炎抗原主要涉及D型肝炎病毒的複製,而大型D型肝炎抗原則是參與D型肝炎病毒的裝配及釋放,以及抑制D型肝炎病毒RNA的複製。
D型抗原有些轉譯後修飾(posttranslational modification),包括甲基化,乙醯化及磷酸化,其中,在大型D型肝炎抗原上異戊二烯化(isoprenylation)對於D型肝炎病毒的裝配及釋放有極重大的影響。我們實驗室曾證實,大型D型肝炎抗原可透過異戊二烯化來活化Twist的啟動子,進而引起TGF-β並引發上皮-間質轉化(EMT),而這樣的機制可能促使肝纖維化、肝硬化及肝癌,而此現象可透過statin藥物(statin為一種降血脂的臨床用藥,能透過抑制HMG-CoA的還原劑來抑制異戊二烯化)抑制大型D型抗原的異戊二烯化來得到改善。
D型肝炎病毒的感染不能缺少B型肝炎病毒提供外套抗原,然而,在我們先前研究statin藥物對於D型肝炎病毒的複製及上皮-間質轉化的效果卻只用大型D型肝炎抗原質體(plasmid)轉染進Huh 7細胞中,B型肝炎病毒並未參與其中。因此在這篇研究,我們使用大型D型肝炎抗原或D型肝炎病毒的質體與B型肝炎表面抗原或B型肝炎病毒的表現質體共同感染Huh 7細胞,我們證實出透過simvastatin藥物的治療可抑制大型D型肝炎抗原,導致抑制D型肝炎病毒的裝配及釋放,並減少TGF-β的釋放及上皮-間質轉化的發生。由於B型及D型肝炎病毒具有高度物種特異性,只能與在人類肝細胞上的特異性NTCP受體結合(一種只會出現在人類肝細胞上的跨模運輸蛋白),因此在建立體內實驗的動物模式時就顯得困難許多。本篇研究我們運用含有人類肝細胞的FRG小鼠,將其感染B型肝炎病毒及超感染D型肝炎病毒用來研究,看肝臟發炎及上皮-間質轉化是否能在使用simvastatin藥物治療後被抑制,而從我們實驗初步的結果得知,透過simvastatin藥物治療後,B型肝炎病毒及D型肝炎病毒在FRG小鼠的血清中減少。本研究顯示,statin類藥物作為治療慢性D型肝炎的新療法可能具有很大的潛力。
Abstract

Hepatitis D virus (HDV) is a defective RNA virus that requires the help of hepatitis B virus (HBV) for viral assembly and transmission. Through persistent hepatic inflammation, HDV infection could cause chronic infection, liver cirrhosis, and hepatocellular carcinoma (HCC). Although HDV infection can be prevented by HBV vaccine, there is no effective and curative therapy for chronic HDV infection till now.
Moreover, previous studies show that HBV replication may be suppressed by HDV. Although the mechanism of HDV interacting with HBV is not clear, it should consider the effect of HBV at the same time when studying the virology of HDV.
The HDV RNA encodes two forms of hepatitis D antigen (HDAg), the large HDAg (L-HDAg) and small HDAg (S-HDAg). Both of these two HDAg play important roles in regulating the life cycle of HDV. Preview studies show that the S-HDAg involves the HDV RNA replication, whereas the L-HDAg takes part in the assembly and release of HDV; and the inhibition of HDV RNA replication.
There is some posttranslational modifications at HDAg, including methylation, acetylation, and phosphorylation. Among them, isoprenylation at L-HDAg is crucial for HDV assembly and release. Our previous data show that L-HDAg can affect TGF-β and induce epithelial-mesenchymal transition (EMT) by acting the Twist promoter, and may also lead liver fibrosis, cirrhosis, and HCC. The interaction of L-HDAg with Twist promoter may be inhibited by statin, which is a hypolipidemic drug inhibiting the isoprenylation by suppressing the HMG-CoA reductase in the clinical treatment.
HDV infection could not work without the help of HBV to provide the surface proteins. However, our previous experiments investigated the treatment efficacy of statins in the HDV replication and EMT only by the transfection of the L-HDAg plasmid into Huh7 cells, and HBV infection was not involved in that study. In this current study, we co-transfected HBsAg or whole HBV plasmid and L-HDAg or whole HDV plasmid into the Huh7 cells and then treated with simvastatin. We confirmed that simvastatin treatment decreased the expression of L-HDAg, in which lead to the reduction of HDV assembly and release, and the secretion of TGF-β and EMT. Because the HBV and HDV contain highly species specificity that restricts the entry of both viruses into hepatocytes only through the species-specific sodium taurocholate cotransporting polypeptide (NTCP), which is a multiple transmembrane transporter only expressed in the human liver. It is difficult to establish an in vivo infection experiment of the animal model. In this study, we carried out infection of HBV and to HDV RG mice which contain human liver cells and study of both viruses and enter human hepatocytes, complete replication and final secretion of HBV and HDV virions in serum, we also studied if liver inflammation and epithelia-mesenchymal transition (EMT) would be decreased by the administration of simvastatin. Our preliminary data showed that HBV and HDV were reduced in serum by the treatment of simvastatin. This study demonstrated that statin may have a great potential to serve as a novel therapy for the treatment of chronic hepatitis D.
Contents

Contents 1
Abstract 3
摘要 5
Lift of Abbreviations 7
Introduction 8
Introduction 9
I. Hepatitis D virus (HDV) 9
II. The structure of HDV 10
III. The replication of HDV 11
IV. The posttranslational modification of HDV antigen 15
V. Genotype of HDV 16
VI. Treatment and prevention 17
VII. Transforming Growth Factor (TGF-β) and Epithelial-mesenchymal transition (EMT) 18
VIII. Statin 18
Rational 20
Hypothesis 21
Aims 22
Experimental designs 23
Materials and methods 25
Cell culture 26
Western blot analysis 33
Northern blot analysis 37
Southern blot analysis 41
ELISA detect for analysis TGF-β 45
FRG mice 47
Statistical analysis 47
Results 48
I. Simvastatin inhibited the release of L-HDV to the medium. 49
II. Simvastatin retained the HDV in the Huh7 cells. 49
III. The HDV which retained in the Huh7 cells seemed not to inhibit the replication of HBV. 50
IV. Simvastatin repressed the secretion of TGF-β and the activity of EMT. 51
V. The effects of simvastatin treatment on serum, HBV and HDV levels of the HDV-superinfected FRG mice which contain the human liver cells. 51
References 56
Figures 70
Figure 1. The expression levels of L-HDAg protein after simvastatin treatment in the medium. 71
Figure 2. The expression levels of HDV mRNA after simvastatin treatment in HBV and HDV-expressing Huh7 cells. 72
Figure 3. The expression levels of HDAg proteins in HBV and HDV-expression plasmids cotransfected Huh7 cells after simvastatin treatment. 73
Figure 4. The expression levels of HDAgs in the medium after simvastatin treatment. 75
Figure 5. The retention ratio of HDAg after simvastatin treatment in the HBV and HDV-expressing Huh7 cells to the medium after simvastatin treatment. 77
Figure 6. The expression levels of HBV DNA in HBV and HDV-expression plasmids cotransfected-Huh7 cells after simvastatin treatment. 80
Figure 7. The expression levels of HBsAg protein in the medium after simvastatin treatment. 81
Figure 8. The levels of TGF-β in the medium after simvastatin treatment. 83
Figure 9. The expression levels of EMT markers and regulators after simvastatin treatment in HBV and HDV-expressing HuH7 cells. 84
Figure 10. The serum HBV and HDV levels of FRG mice after HDV superinfection and treatment with simvastatin. 86
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