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研究生:莊懷堯
研究生(外文):Huai-Yao Chuang
論文名稱:建立一快速且便利的方式以增強轉殖基因在特定細胞中的表現
論文名稱(外文):Development of a rapid and convenient method to enhance the transgenic expression in target cells
指導教授:廖光文
指導教授(外文):Kuang-Wen Liao
學位類別:碩士
校院名稱:國立交通大學
系所名稱:生物科技系所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:英文
論文頁數:100
中文關鍵詞:癌症基因治療專一性指向傳遞系統胜�托�向轉錄因子合成啟動子
外文關鍵詞:cancer gene therapyspecific targetingdelivery systempeptide targetingtranscription factorsynthetic promoter
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基因治療對癌症病患提供了前所未有的治療策略及希望。不幸的是,無論是基因傳遞或啟動子系統迄今仍未達到專一性之療效,除此之外,任一系統的最佳化都極端困難。在本研究中我們希望介紹一個簡單的概念:亦即部分專一的基因傳遞系統以及部分專一的啟動子相結合,將可對標靶細胞達到更加專一性的表現。在第一部分,我們首先檢測與腫瘤相關的轉錄因子在腫瘤或快速生長細胞中的活性。接著利用表現量較高的轉錄因子(NF-kB,CREB以及HIF-1)之反應片段,取三倍體構築一轉錄因子相關之合成啟動子(Transcription factor-based synthetic promoter,TSP) 。實驗結果證實TSP在特定細胞中具有活性並有部分專一性。此外相對於NF-�羠 或HIF-1迷你啟動子,TSP在抑制劑存在之下表現較佳的抵抗性。 在第二部分,多功能胜�吐GD-4C-HA可專一性結合至B16-F10細胞表面之integrin alphavbeta3並且吸附至聚乙烯亞胺(Polyethyleneimine,PEI)。實驗結果顯示RGD-4C-HA能與聚乙烯亞胺形成複合物並且在in vitro實驗中引導專一性的指向。最後,聚乙烯亞胺及胜�汗あX物與TSP的結合能夠使轉殖基因專一性的表現在B16-F10細胞中。這種策略在in vitro實驗中已經證實為可行,並且在in vivo的專一性基因治療可能也具有潛力。
Gene therapy provides a novel strategy and a new hope for the patients with cancer. Unfortunately, the specificity of the delivery systems or the promoters did not achieve the specific efficacy so far and the perfection of either system will be extremely difficult. In this study we had introduce a simple concept that the combination of partial specific delivery and partial specific promoter activity may achieve more specific effect for specific expression in target cells. In the first part, the tumor related transcription factors were assayed in tumor or rapid-proliferating cells to determine their activities. The activities of NF-�羠, CREB, and HIF-1 were higher and three copies of each response elements were used to construct a transcription factor-based synthetic promoter (TSP). The results showed that the expression of TSP was truly active and partial specific to cell types. In addition, it was more resistant than NF-kB or HIF-1 mini-promoters at the presence of inhibitors. In the second part, the multi-functional peptide RGD-4C-HA was designed to specifically target integrin alphavbeta3 on B16-F10 cells and absorbed to polyethyleneimine (PEI) molecules. The results showed that RGD-4C-HA could associate with PEI to form complex and mediate specific targeting in vitro. Finally, the combination of PEI-peptide complex and TSP could enhance the specifically transgenic expression in B16-F10 cells. This strategy had been proven to work in vitro and might be also potential in specific gene therapy in vivo.
Contents
Abstract in Chinese………………………………………………i-ii
Abstract………………………………………………………………iii
Acknowledgements………………………………………iv
Contents…………………………………………………v-ix
List of tables………………………………………………………x
List of figures………………………………………………………xi
Abbreviations…………………………………………………………xii

Chapter 1 Introduction

1.1 Cancer gene therapy…………………………………………1
1.2 Delivery system for cancer gene therapy…………………3
1.2.1 Viral vectors……………………………………3
1.2.2 Non-viral methods………………………………3
1.2.2.1 Polyethyleneimine (PEI)………………………………5
1.3 Promoters for cancer gene therapy…………………………6
1.3.1 Cancer specific promoters…………………………………7
1.3.2 Tumor related promoters……………………………………8
1.4 Activities of NF-�畿, HIF-1, and CREB in cancer progression and therapy……9
1.4.1 Transcription factor binding sites for expression…10
1.4.2 Nuclear factor-kappaB (NF-�羠).………11
1.4.2.1 Biology of NF-�羠………………………………………12
1.4.2.2 NF-κB in cancer progression………………………13
1.4.3 Hypoxia-inducible factors (HIFs)………………15
1.4.3.1 Biology of HIFs…………………………………………16
1.4.3.2 HIFs in cancer progression…………………………16
1.4.4 cAMP response-element binding protein (CREB)……16
1.4.4.1 Biology of CREB…………………………………………17
1.4.4.2 CREB in cancer progression…………………………18
1.4.5 Transcription factors interaction in cancer progression…18
1.5 Strategy.……………………………………………………19

Chapter 2 Materials and Methods

2.1 Materials………………………………………………21
2.1.1 Primers ………………………………………………21
2.1.2 Cell lines …………………………………………21
2.1.3 Plasmids ……………………………………………22
2.1.4 Chemicals, enzymes, and reagents ……………23
2.1.5 Antibodies……………………………………………30
2.1.6 Kits…………………………………………30
2.1.7 Buffers ………………………………………………31
2.1.8 Media …………………………………………………33
2.1.9 Equipment ……………………………………………34
2.2 Methods………………………………………………………56
2.2.1 Construction of transcription factor-based synthetic promoter (TSP).56
2.2.1.1 Restriction enzyme digestion…………………57
2.2.1.2 DNA extraction…………………………58
2.2.1.3 Ligation……………………………………58
2.2.2 Transformation of E. coli………………………58
2.2.2.1 Preparation of competent cells for heat shock………58
2.2.2.2 Transformation of competent cell by heat shock method……59
2.2.3 Plasmid DNA extraction …………………………………59
2.2.3.1 Minipreparation method……………………………60
2.2.3.2 Midipreparation method…………………………61
2.2.4 Cell culture ……………………………………………62
2.2.4.1 Procedures of subculture……………………………62
2.3 Transcription factors and TSP activity assay……………………43
2.3.1 Transfection of mammalian cells……………………44
2.3.1.1 Seeding cells…………………………………………44
2.3.1.2 Polyethyleneimine transfection……………………44
2.3.1.3 LipofectamineTM 2000 transfection…………………45
2.3.2 Measurement of reporter gene expression by flow cytometry…46
2.4 RGD-4C-HA binding assay……………………………………46
2.5 The absorption of RGD-4C-HA to PEI assay………………………47
2.5.1 Separating PEI-peptide complex with un-absorbed PEI and RGD-4C-HA by gel filtration column S-200.………………47
2.5.2 Ninhydrin test……………………………………………48
2.5.3 Dot-blotting……………………………………………48
2.6 PEI-peptide complex transfection……………………49
2.7 Statistical analysis……………………………………49

Chapter 3 Results

3.1 Establishment of the transcription factor-based mini promoter (TSP) system………………………50
3.1.1 Screening of the activities of several transcription factors in different cells……………50
3.1.2 Construction of the transcription factor-based synthetic promoter (TSP)………………………51
3.1.3 Transcription factor-based mini promoter activity in different cells…………………………52
3.1.4 Inhibition effect of TSP in HeLa cells………………………53
3.2 Design of RGD-4C-HA and the functional regions…………………54
3.3 The binding affinity of RGD-4C-HA………………………………55
3.4 The absorption of RGD-4C-HA to PEI………………………………57
3.5 The enhancement of transgenic expression by PEI-peptide complex……………………………………58
3.6 The enhancement of transgenic expression by PEI-peptide complex (HIF-1)…………………………58
3.7 Enhancement of transgenic expression by PEI-peptide complex combined with TSP in B16-F10 cells…………………60

Chapter 4 Discussion………………………………61

References……………………………………………78

Appendices……………………………………………87
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