請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/8014完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林淑華(Shu-Wha Lin) | |
| dc.contributor.author | Kuang-Yen Chen | en |
| dc.contributor.author | 陳光彥 | zh_TW |
| dc.date.accessioned | 2021-05-19T18:02:47Z | - |
| dc.date.available | 2024-07-31 | |
| dc.date.available | 2021-05-19T18:02:47Z | - |
| dc.date.copyright | 2014-10-09 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-08-01 | |
| dc.identifier.citation | Birnbaum, F., and Nassal, M. (1990). Hepatitis B virus nucleocapsid assembly: primary structure requirements in the core protein. Journal of virology 64, 3319-3330.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/8014 | - |
| dc.description.abstract | Hepsin為第二型穿膜絲胺酸蛋白酶，主要表現於肝臟。試管實驗已證實Hepsin可活化人類第七凝血因子及肝細胞生長因子前驅物等受質，故推測 Hepsin可能參與血液凝固與肝細胞生長。先前文獻利用共免疫沉澱實驗發現，Hepsin與B型肝炎病毒 (hepatitis B virus；HBV)的轉錄活化因子HBx有交互作用，由於HBx被認為可促進HBV的複製，且當含HBV基因體的肝癌細胞株HepG2.2.15共轉染Hepsin與HBx時，細胞培養液中HBeAg (hepatitis B early antigen，可作為病毒複製指標)的含量上升，因此Hepsin被推測能促進病毒複製。本篇論文欲利用基因剔除小鼠模式探討Hepsin對HBV複製的影響；為確認Hepsin相關功能區與HBV病毒複製關係，也建立了攜帶Hepsin cDNA的腺相關病毒 (adeno-associated virus，AAV)及肝臟大量表現人類 Hepsin的基因轉殖小鼠 (Tg-hHPN)等動物模式。由於小鼠肝細胞無法自然感染HBV，本論文首先以尾靜脈高壓注射法 (hydrodynamic injection)將HBV質體DNA注射入同窩野生型 (wild-type littermate，WT)小鼠與HPN基因剔除 (hepsin knockout，HPN KO)小鼠，使小鼠肝細胞製造HBV後，比較兩組小鼠間血清及肝臟中HBV病毒量。確認尾靜脈高壓注射法於肝細胞轉染效率一致的作法，是以抗HBcAg (hepatitis B core antigen)免疫螢光染色完成，證明WT及HPN KO小鼠的肝切片中表現HBcAg陽性肝細胞數目相近。後續分析顯示，雖然兩組小鼠血清中HBsAg (hepatitis B surface antigen)與HBeAg無差異，但Q-PCR定量發現HPN KO小鼠血清HBV DNA約少WT小鼠2倍，且兩組小鼠的肝細胞HBV DNA量相當；因此推測Hepsin對於肝細胞內HBV複製影響有限，而可能與病毒由肝細胞釋放有關。此外利用AAV感染的方式於HPN KO小鼠肝臟表現野生型及各功能區突變後，初步顯示表現野生型Hepsin的HPN KO小鼠，血清中HBV DNA量較高。為了免於AAV感染系統下的Hepsin表現量差異過大，另外利用原核顯微注射技術建立了表現Hepsin野生型及各功能區突變型共3種品系的Tg-hHPN小鼠，其中2品系的種源小鼠 (founder)已確認在肝臟大量表現Hepsin，目前正進行子代配種及子代Hepsin表現量分析，未來將建立穩定傳系且表現量高的Tg-hHPN小鼠，用於後續研究。 | zh_TW |
| dc.description.abstract | Hepsin is a type II transmembrane serine protease predominantly expressed in the liver. In vitro study showed that hepsin can activate human coagulation factor VII and hepatocyte growth factor precursor. This may imply that hepsin is involved in liver development and coagulation. A literature showed hepsin interacted with the trans-activator factor HBx of hepatitis B virus in co-immunoprecipitation assay. HBx was considered to promote HBV (hepatitis B virus) replication, and the expression of HBeAg (hepatitis B early antigen, an indicator of HBV replication) was increased in HBV-genome positive hepatoma cell line, HepG2.2.1.5, when Hepsin and HBx were co-expressed in the cells. Therefore, hepsin was indicated to stimulate HBV replication. This thesis tried to investigate the role of Hepsin in HBV replication using hepsin-deficient mice (HPN KO mice). Moreover, we established an adeno-associated virus (AAV) delivery system and the transgenic mouse models which expressed human Hepsin (Tg-hHPN) in the liver to validate the importance of Hepsin in HBV replication. Since HBV can not directly infect mouse hepatocyte, we used hydrodynamic injection to deliver HBV plasmid DNA into WT and HPN KO mice for establishing HBV replication in mice hepatocytes. Both strains of mice showed nearly equivalent amount of HBcAg (hepatitis B core antigen) expressing cells as detected by immunohistochemistry, suggesting that the efficiency of hydrodynamic injection was similar between WT and HPN KO mice. Subsequent analysis revealed that serum HBsAg (hepatitis B surface antigen) and HBeAg levels had no significant differences, but the serum HBV DNA levels in HPN KO mice were 2 times lower than those in WT mice. However, the hepatic HBV DNA levels were similar in WT and HPN KO mice. This observation suggested that Hepsin is associated with HBV secretion or assembly. Furthermore, the preliminary data showed that expression of wild-type hepsin in HPN KO mice using AAV-delivery system seems to enhance the serum HBV DNA levels. Besides, we established three different lines of Tg-hHPN mice, including wild-type and the functional domain mutant Hepsin transgenic mice. So far, two of these transgenic lines had the founder mice withthe expression of Hepsin in liver for offspring breeding. We will screen and establish the stable and high-level expression of human HPN Tg-hHPN mice for further studies. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-19T18:02:47Z (GMT). No. of bitstreams: 1 ntu-103-R01424027-1.pdf: 3475112 bytes, checksum: 38b2b4eab25437fc084fa97ca70056b8 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 論文口試委員審定書....................ii
誌謝...............................................iii 中文摘要.......................................iv 英文摘要.......................................vi 圖目錄...........................................ix 表目錄............................................x 緒論................................................1 材料方法........................................8 實驗結果......................................17 討論..............................................22 參考文獻......................................27 附錄..............................................59 | |
| dc.language.iso | zh-TW | |
| dc.title | 利用小鼠模式研究Hepsin與B型肝炎病毒量的相關性 | zh_TW |
| dc.title | Study of association of Hepsin with hepatitis B virus levels
in mouse models | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 吳慧琳(Hui-Lin Wu),游益興(I-Shing Yu),楊雅倩(Ya-Chien Yang) | |
| dc.subject.keyword | Hepsin基因剔除小鼠,尾靜脈高壓注射法,B型肝炎病毒,腺相關病毒,基因轉殖小鼠, | zh_TW |
| dc.subject.keyword | Hepsin Knockout mice,Hydrodynamic injection,Hepatitis B virus,Adeno-associated virus,transgenic mice, | en |
| dc.relation.page | 60 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2014-08-01 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| dc.date.embargo-lift | 2024-07-31 | - |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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