請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/23123完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 吳金洌(Jen-Leih Wu) | |
| dc.contributor.author | Chien-Yuan Lin | en |
| dc.contributor.author | 林健淵 | zh_TW |
| dc.date.accessioned | 2021-06-08T04:43:05Z | - |
| dc.date.copyright | 2009-08-20 | |
| dc.date.issued | 2009 | |
| dc.date.submitted | 2009-08-05 | |
| dc.identifier.citation | 1.Higginson J: The Geographical Pathology of Primary Liver Cancer, Cancer Res 1963, 23:1624-1633
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I | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/23123 | - |
| dc.description.abstract | Hepatitis B virus (HBV) X protein (HBx) can transactivate proto-oncogene, induce protein kinase signaling pathway and interact with numerous cellular protein, as p53 and hTRET. Studies all showed the potential role of HBx to promote HBV-related hepatocellular carcinoma (HCC); however, the role of HBx play in the pathogenesis of HCC is still enigma. Some reports suggested there is a threshold level of HBx in HCC development. The rapid degradation of HBx by the proteasome pathway, which is one character of HBx protein, will lead to the low concentration of HBx. By the way, there are also inconsistent data in both in vitro result and HBx transgenic mouse in vivo models. Conditional expression system (Tetracycline (Tet)-inducible) is adopted to highly and specifically express HBx in the liver of zebrafish, here, we try to reveal the role of HBx in liver pathology and also reflect to the high level of HBx in the clinical case. We established a liver disease model by using zebrafish and explained the possible mechanism of HBx involved in pathogenesis of HCC, from the hepatocyte apoptosis to the liver disease progression. For performance of the Tet-inducible system in vivo, we first tested the toxicity of doxycycline (Dox) in zebrafish and 100μg/ml is highest dosage for induction without severe toxicity. Later, 30μg/ml is chosen as the default concentration for the induction assay and the inducible expression pattern is successfully and efficiently achieved in our in vivo model. In the liver pathology, human liver disease progression, as inflammation, fibrosis and HCC phenotype, can also be observed in the transgenic zebrafish by using H&E staining. By the induction of TGF-β expression in the liver, we hypothesis the apoptotic capacity of HBx may play an important role in the HBV- related liver disease progression. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T04:43:05Z (GMT). No. of bitstreams: 1 ntu-98-R96b47103-1.pdf: 10187491 bytes, checksum: bad7515487fb04a5e8f5f93fdaf1835f (MD5) Previous issue date: 2009 | en |
| dc.description.tableofcontents | 1 Introduction ............................................................................................4
1.1 Discovery of Hepatitis B virus (HBV) ......................................................4 1.2 Introduction of HBV ..............................................................................5 1.3 Clinical data of HBx in the HBV infection ................................................6 1.4 The published system of HBx transgenic models ....................................7 1.5 The well known functions of HBx ...........................................................9 1.6 The unique approach in our study about HBx ........................................10 1.7 Good advantages by using zebrafish as the liver disease model ..............11 1.8 The unsolved questions of HBx ............................................................13 1.9 TGF-β and TNF-α induce apoptosis in hepatocyte .................................14 1.10 The approach and finding in this study ................................................15 2 Materials and methods ..........................................................................18 2.1 Fish maintenance ...............................................................................18 2.2 Plasmid constructions ........................................................................18 2.3 Microinjection ....................................................................................19 2.4 Transient embryonic excision assay (TEEA) .........................................19 2.5 Fluorescence microscope observation ..................................................20 2.6 RNA extraction ..................................................................................20 2.7 cDNA synthesis .................................................................................21 2.8 Quantitative polymerase chain reaction (qRT-PCR) ................................22 2.9 GFP regulation assay .........................................................................22 2.10 Western blot detection ......................................................................22 2.11 Liver histological analysis ..................................................................23 2.12 Terminal dUTP nick end labeling (TUNEL) assay .................................23 2.13 Immunohistochemistry (IHC) ..............................................................24 3 Results ................................................................................................25 3.1 Constructions of Tet-off expression system in zebrafish .........................25 3.2 Integration and transmission ratio in Tet-off system ...............................27 3.3 Transmission rate of F1, F2 and F3 transgenic zebrafish .......................28 3.4 High concentration of doxycycline is toxic to zebrafish ..........................29 3.5 High concentration of doxycycline delays the timing of hatching out .......31 3.6 Tet-inducible system is fully functional in vivo .......................................32 3.7 Modulation of GFP expression level by DOX induction ...........................34 3.8 GFP regulation profile is affected by the age of fish ...............................36 3.9 Selection of the Tet-off HBx founder fish ...............................................37 3.10 Dosage-dependent regulation of HBx expression by DOX .....................39 3.11 Western blotting for detection of HBx protein ......................................40 3.12 The indirect evidences for HBx expression ..........................................41 3.13 Liver histological analysis of the WT, VC and the HBx transgenic fish ...42 3.14 TUNEL assay for apoptosis event detection ........................................46 3.15 Mechanism study for liver injury caused by HBx ..................................48 4 Discussions .........................................................................................50 4.1 Tet-off HBx transgenic zebrafish establishment .....................................50 4.2 Transmission ratio of F0, F1 and F2 transgenic zebrafish ......................52 4.3 Toxicity test of the doxycycline ...........................................................54 4.4 Regulation of GFP expression in HBx transgenic fish liver .....................55 4.5 Regulation of HBx expression level by different dosage of DOX ...............57 4.6 Western blotting for HBx protein ..........................................................58 4.7 HBx-induce malignant phenotype in the liver of transgenic zebrafish .......59 4.8 The role of HBx in tumorigenesis .........................................................65 5 References ...........................................................................................69 6 Figures ................................................................................................87 Figure 1 Construction map for Tet-off system ..............................................87 Figure 2. Transient embryonic excision assay (TEEA) .................................88 Figure 3. In vivo observation of the GFP expression in zebrafish liver .............89 Figure 4. Doxycycline (DOX) Toxicity test ..................................................90 Figure 5. Inhibition of embryos hatch-out rate during DOX treatment .............91 Figure 6. GFP expression pattern during DOX induction ..............................92 Figure 7. Regulation profile of Tet-off system is dosage-dependent ...............94 Figure 8. Age of the fish affect the GFP regulation profile ............................95 Figure 9. Tet-off HBx founder fish selection ................................................96 Figure 10. Analysis of HBx transcript by RT-PCR .......................................97 Figure 11. HBx mRNA detection in transgenic fish and control fish ...............98 Figure 12. Expression of HBx by different dosage of DOX induction ..............99 Figure 13. Liver section of six-month-old WT fish (H & E) ...........................100 Figure 14. Liver section of 12-month-old WT fish (H & E) ............................101 Figure 15. Liver section of 6-month-old VC fish (H & E) ..............................102 Figure 16. Liver section of 6-month-old HBx transgenic fish (H & E) ............103 Figure 17. Population of Hepatocyte increased in HBx transgenic fish .........104 Figure 18. Liver section of 7-month-old HBx transgenic fish (H & E) ............105 Figure 19. Liver section of 7.5-month-old HBx transgenic fish (H & E) .........106 Figure 20. Liver section of 9-month-old HBx transgenic fish (H & E) ............107 Figure 21. Apoptosis events accompanied liver disease (TUNEL assay) ......108 Figure 22. IHC detection for TNF-α in zebrafish with liver disease ...............109 Figure 23. TGF-β and TNF-α are elevated in the inflamed HBx fish liver .......110 Figure 24. Correlated expression pattern of between HBx and TGF-β ..........111 7 Table .................................................................................................112 Table 1. The established HBx mouse transgenic model .............................112 Table 2. The conflict in vitro data of HBx ...................................................113 Table 3. Primer for the qRT-PCR ..............................................................114 Table 4. Transmission rate of F0 fish ........................................................115 Table 5. Transmission rate of F1 fish ........................................................116 Table 6. Transmission rate of F2 fish ........................................................117 Table 7. Criteria of HCC in zebrafish .........................................................118 Table 8. Criteria of HCC in other fish species .............................................119 | |
| dc.language.iso | en | |
| dc.subject | 肝臟疾病模式動物 | zh_TW |
| dc.subject | X 蛋白 | zh_TW |
| dc.subject | 肝細胞癌 | zh_TW |
| dc.subject | 活體觀測 | zh_TW |
| dc.subject | 四環黴素誘導系統 | zh_TW |
| dc.subject | Tetracycline-inducible system | en |
| dc.subject | liver disease | en |
| dc.subject | HBx | en |
| dc.subject | HCC | en |
| dc.subject | in vivo imaging | en |
| dc.title | 肝臟專一性表現 HBx 促進斑馬魚模式生物肝癌的形成 | zh_TW |
| dc.title | Liver specific and inducible expression of HBx promote tumorigenesis in zebrafish | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 97-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳俊叡(Jim-Ray chen),陳俊任(Chun-Jen Chen),邱品文(Pin-Wen Chiou) | |
| dc.subject.keyword | X 蛋白,肝細胞癌,活體觀測,四環黴素誘導系統,肝臟疾病模式動物, | zh_TW |
| dc.subject.keyword | HBx,HCC,in vivo imaging,Tetracycline-inducible system,liver disease, | en |
| dc.relation.page | 119 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2009-08-05 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 微生物與生化學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
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