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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 李宣書 | |
dc.contributor.author | Tsai-Shin Chiang | en |
dc.contributor.author | 蔣采昕 | zh_TW |
dc.date.accessioned | 2021-06-16T16:30:41Z | - |
dc.date.available | 2015-01-16 | |
dc.date.copyright | 2013-01-16 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-12-24 | |
dc.identifier.citation | Abu-Absi, S. F., Friend, J. R., Hansen, L. K., and Hu, W. S. (2002). Structural polarity and functional bile canaliculi in rat hepatocyte spheroids. Exp Cell Res 274, 56-67.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/63250 | - |
dc.description.abstract | 準確有效且方便的藥物代謝與毒性預測之篩選平台對於新藥開發是非常重要,然而目前卻仍然缺乏。本研究首先選用24個對於肝臟再生與發育相當重要的轉錄因子 (transcription factors) 與核受體 (nuclear receptors),並最後篩選出10個轉錄調控因子,能誘導人類皮膚纖維母細胞 (human dermal fibroblasts, HDFs) 表現 phase I 藥物代謝的重要酵素:cytochrome P450 (CYP) 3A4、1B1 與 2C9。誘導後的人類皮膚纖維母細胞之CYPs的基因表現量與活性均高於目前普遍使用的肝癌細胞株 (hepatoma cell lines)。藉由將誘導後的細胞培養成球體或將細胞種入不同類型的三維細胞支架材料,尤其是由明膠 (gelatin)、軟骨素 (chondroitin) 和透明質酸 (hyaluronan) 所組成的三共聚物材料可以更進一步的增加CYPs的基因表現量與活性。值得注意的是,誘導後的細胞培養成球體並種入三共聚物材料對於增加CYPs的基因表現量與活性具有顯著的加乘效應。掃描式電子顯微鏡和共軛焦顯微鏡顯示,這些細胞球體能穩定的存在三維細胞支架材料內部並且展現高度存活率。此外,球體之細胞培養於三維細胞支架材料中,具有能將高血壓藥物-硝苯地平 (nifedipine) 代謝成氧化硝苯地平 (oxidized nifedipine) 之能力,顯示此平台可適用於藥物代謝之研究。本研究提出了一項新策略,能誘導人類皮膚纖維母細胞表現phase I 藥物代謝的重要酵素之基因且具有活性,未來將有助於建立體外藥物代謝的研究平台可用於預測藥物對人體的毒性。 | zh_TW |
dc.description.abstract | A reliable, reproducible, and convenient in vitro platform for drug metabolism determination and toxicity prediction is of tremendous value but still lacking. In the present study, a collection of 24 hepatic transcription factors and nuclear receptors in different combinations were surveyed, and 10 among them were finally selected to induce the expression and enzyme activities of cytochrome P450 (CYP) 3A4, 1B1, and 2C9 in human dermal fibroblasts (HDFs). The expression and activities of these CYPs in the induced HDFs were higher than those in commonly used hepatoma cell lines. Even higher CYP expression and activities could be further enhanced by culturing the induced HDFs either as spheroids or into several kinds of scaffolds, particularly the tri-copolymer scaffold composed of gelatin, chondroitin, and hyaluronan. More strikingly, there showed a synergistic effect of seeding and culturing the spheroids into the tri-copolymer scaffold. Scanning electron microscopy and confocal microscopy disclosed well accommodation of these spheroids inside the scaffolds and displayed a high survival rate. Moreover, the spheroid/scaffold constructs could metabolize an anti-hypertension drug nifedipine into oxidized nifedipine, showing their applicability in studying drug metabolism. This study presents a novel strategy to induce the expression and enzyme activities of critical CYPs in HDFs, and may have potential to establish an in vitro platform to study drug metabolism and to predict the possible human risk of drug toxicity. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T16:30:41Z (GMT). No. of bitstreams: 1 ntu-101-D97642003-1.pdf: 1513712 bytes, checksum: 6dc199fc63c00079aaf150d3e13da2e1 (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | 中文摘要 ii
Abstract iv Table of Contents vi List of Figures xi List of Tables xiii Abbreviations xiv Chapter 1. Introduction 1 1.1 An overview of drug metabolism 1 1.1.1 Phase I, phase II metabolism enzymes and phase III transporters in drug biotransformation process 4 1.1.2 The role of the hepatocyte in biotransformational system 8 1.2 An introduction to drug metabolism prediction 9 1.2.1 The importance of drug metabolism prediction 9 1.2.2 In vivo drug screening platform to study drug metabolism 10 1.2.3 In vitro drug screening platform to study drug metabolism 11 1.2.3.1 Human liver microsomes (HLM) 11 1.2.3.2 Human liver slices 13 1.2.3.3 Human liver S9 fractions 13 1.2.3.4 Human hepatoma cell lines 14 1.2.3.5 Human primary hepatocytes 16 1.3 Human cytochrome P450 (CYPs) families and their regulation 19 1.3.1 Properties of human CYPs 19 1.3.1.1 CYP1A families 20 1.3.1.2 CYP1B families 20 1.3.1.3 CYP2C families 21 1.3.1.4 CYP2E families 21 1.3.1.5 CYP3A families 22 1.3.2 Regulation of the CYP gene expression 24 1.4 Monolayer and three-dimensional (3D) culture microenvironments 27 1.5 The goals of this study 30 Chapter 2. Materials and Methods 32 2.1 Cell culture 32 2.2 Flow cytometric analysis 32 2.3 Plasmid construction and production of recombinant lentiviruses 33 2.4 Titration of produced lentiviruses by flow cytometry 34 2.5 Induction of HDFs by lentivirus infection 35 2.6 Total RNA isolation, reverse transcription, and quantitative-polymerase chain reaction (Q-PCR) 35 2.7 Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis 36 2.8 CYP activity assays 37 2.9 Fabrication of scaffolds 38 2.10 Seeding cells into scaffolds 38 2.11 Preparation of scaffold for scanning electron microscopy 39 2.12 Live/Dead assay of cells cultured as spheroids 39 2.13 CYP3A4 activity assay by measuring metabolized nifedipine (NIF) 40 2.14 Statistics 42 Chapter 3. Results 43 3.1 Characterization of HDFs by flow cytometry 43 3.2 Lentivirus-mediated protein expression of target genes in human kidney 293T cells 44 3.3 Selection of 10 from 24 factors optimally inducing CYP3A4 expression in HDFs 45 3.4 The morphological change from HDFs to 10F-HDFs 47 3.5 Comparing 10F-HDFs with human hepatoma cell lines regarding their gene expression and enzyme activities of CYP3A4, CYP1B1 and CYP2C9 48 3.6 The relationship between initial seeding density and the size of spheroid of 10F-HDFs 49 3.7 Determination of optimal culture conditions for spheroid formation of 10F-HDFs 51 3.8 Enhancement of CYP3A4 expression in 10F-HDFs cultured in various kinds of scaffolds 52 3.9 Further enhancement of the gene expression and enzyme activities of CYPs in 10F-HDFs cultured as spheroids and seeded inside the GCH tri-copolymer scaffold 53 3.10 Demonstration of 10F-HDF spheroids accommodated within the GCH tri-copolymer scaffold 55 3.11 Persistence of enhanced CYP3A4 expression and activities in the spheroid-scaffold cultures for 2 weeks 56 Chapter 4. Discussion 57 Chapter 5. Conclusions 64 Chapter 6. Future perspectives 65 Chapter 7. References 67 Chapter 8. Appendix-Tables 87 Chapter 9. Appendix-Figures 91 Chapter 10. Results in this study-Tables 95 Chapter 11. Results in this study-Figures 98 Chapter 12. Appendix-Published paper 114 | |
dc.language.iso | en | |
dc.title | 藉由轉錄調控因子與三維支架誘導人類皮膚纖維母細胞表現 cytochrome P450 以建立藥物代謝之預測平台 | zh_TW |
dc.title | Induction of cytochrome P450 activities in human dermal fibroblasts by transcriptional regulators and three-dimensional scaffolds for drug metabolism prediction | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 林峰輝,徐善慧,符文美,宋麗英,張晃猷 | |
dc.subject.keyword | 人類皮膚纖維母細胞,細胞色素 P450,轉錄調控因子,三維細胞支架,藥物代謝, | zh_TW |
dc.subject.keyword | Human dermal fi,broblast,Cytochrome P450,Transcriptional regulator,Scaffold,Drug metabolism, | en |
dc.relation.page | 114 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2012-12-24 | |
dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
dc.contributor.author-dept | 生物科技研究所 | zh_TW |
顯示於系所單位: | 生物科技研究所 |
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