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博碩士論文 etd-0725116-122157 詳細資訊
Title page for etd-0725116-122157
論文名稱
Title
操控慢病毒傳遞應用於核糖核酸干擾治療之研究
Remote control of lentivirus for RNA interference therapy
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
78
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2016-08-22
繳交日期
Date of Submission
2016-08-30
關鍵字
Keywords
核糖核酸干擾、小片段干擾型RNA、磁性奈米粒子、慢病毒載體、微觀感染
RNA interference, Short hairpin RNA, Micro-transduction, Lentivirus, Magnetic nanoparticles
統計
Statistics
本論文已被瀏覽 5680 次,被下載 80
The thesis/dissertation has been browsed 5680 times, has been downloaded 80 times.
中文摘要
病毒性載體(Viral vector)在臨床癌症治療中已成功獲得美國食品藥物管理局(FDA)的認可,目前也針對不同種類之病毒進行評估,期許有更多病毒載體能應用於不同癌症治療上,而在創新之癌症治療中,溶瘤病毒 (Oncolytic viruses) 為目前一種新興治療方法。由於HIV-1的慢病毒載體 (Lentivirus) 具有感染分裂和非分裂之細胞、可以穩定地將基因整合至宿主基因組中,並達到長時間轉染基因之表現,進而確立HIV-1病毒家族中的慢病毒載體 (Lentivirus) 在基因治療上之應用。雖然病毒載體已經有顯著抑制腫瘤之效果,但卻無法使病毒載體以全身性傳遞之方式進行治療。因此,在病毒載體之臨床治療上,若能達到有效及準確的傳遞能力,將會拓展病毒載體在臨床治療上之應用能力。
為了提升病毒載體在傳遞上之效益,本實驗加入磁性氧化鐵奈米粒子作為應用,利用化學接合慢病毒載體 (Lentivirus) 形成磁性慢病毒載體,透過外部磁場引導傳遞,使病毒載體快速累積載體於標的位置上,來達到遠程調控微觀定位之表現。為了提升磁性慢病毒載體之應用性,進一步使用小片段干擾型RNA基因 (short hairpin RNA) 來插入至慢病毒載體之基因組中並應用於癌細胞上。藉由慢病毒膜融合之方式感染癌細胞,藉由外部磁鐵吸附下使磁性慢病毒載體累積,將shRNA傳遞到細胞核中進行轉錄,透過RISC (RNA-induced silencing complex) 的蛋白質複合體中結合誘導癌細胞EGFR之基因沉默,促使癌細胞產生凋亡。
Abstract
Clinical virotherapy has been successfully approved for use in cancer treatment by the US Food and Drug Administration (FDA). Innovative treatment of cancer, oncolytic viruses is a new treatment of cancer, with different type of virus families to evaluate different disease in clinical trials and increase viral applications. During the past decade viral vehicles constructed from HIV-1, the best characterized of the lentiviruses, have been established. Lentivirus based on HIV-1 are capable of infecting a wide variety of dividing and non-dividing cells, integrate stably into the host genome, and result in long term expression of the transgene. However, one of the most important technical solutions needed for clinical virotherapy is improved systemic virus delivery. Achieving efficacious and accurate systemic delivery will greatly broaden opportunities in virotherapy. Furthermore, magnetic nanoparticles provide accelerated vector accumulation in target sites when directed with magnetic field-enforced delivery. In this study, we show that lentivirus chemically conjugated with iron oxide nanoparticles (~ 5nm) have remarkable ability to be remotely guided under magnetic field. Transduction is achieved with micro-scale precision. Furthermore, a gene for shRNA (short hairpin RNA) production was introduced into the lentivirus genome to enable RNA interference (RNAi).
目次 Table of Contents
目錄
誌謝 i
中文摘要 ii
ABSTRACT iii
目錄 iv
圖目錄 viii
第一章 緒論 1
1-1 基因治療 1
1-1-1 基因治療概論 1
1-1-2 基因治療與疾病之結合 1
1-1-3 基因治療之治療方法 2
1-2 基因治療之應用 2
1-3 基因傳遞系統 4
1-3-2 非病毒性基因傳遞載體 5
1-3-3 病毒性基因傳遞載體 7
1-4 病毒性載體之應用 8
1-4-1 病毒性載體之臨床發展 9
1-4-2 慢病毒基因傳遞載體 10
1-5 核糖核酸干擾(RNA interference) 13
1-6 EGFR 基因與癌細胞之關係 14
1-7 慢病毒攜帶RNAi (Lentivirus-mediated RNAi) 15
1-8 磁性奈米粒子之介紹 16
1-9 研究之目的 19
第二章 材料與方法 21
2-1 材料 21
2-2 細胞培養 22
2-3 實驗質體製備 22
2-3-1 質體DNA轉型(Transformation)作用 22
2-3-2 質體DNA放大製備 23
2-3-3 質體DNA之純化 23
2-3-4 質體DNA利用瓊膠凝膠電泳檢測(Agarose gel electrophoresis) 24
2-4 慢病毒載體製備 25
2-4-1 前期-質體DNA共轉染實驗 25
2-4-2 後期-純化慢病毒載體 26
2-4-3 純化後慢病毒感染細胞能力檢測 27
2-5 利用磁性奈米粒子接合慢病毒載體 28
2-5-1、 實驗材料之物性測試 29
2-6 材料毒性測試 29
2-7 製備材料最佳化之條件 30
2-8 製備材料最佳化條件及局部磁吸病毒定位之測試 31
2-9 利用抗體染色檢測磁性慢病毒局部磁吸定位之病毒分佈 32
2-10 插入具有功能性基因之慢病毒載體對癌細胞之毒性測試 32
2-11 磁性奈米粒子接合 shRNA 慢病毒載體感染癌細胞後細胞凋亡之檢測 33
2-11-1 磁性shRNA慢病毒定位後以TUNEL染色檢測細胞凋亡之表現 33
2-11-2 磁性shRNA慢病毒定位後以活細胞與死細胞染色之檢測 34
2-12 統計分析 34
第三章 結果與討論 35
3-1 製備慢病毒載體 35
3-1-1由D5α之轉型放大質體DNA 35
3-1-2純化質體DNA之凝膠電泳檢測 36
3-3 四氧化三鐵接合Lentivirus接合之特性 38
3-3-1 共價鍵結形成磁性慢病毒載體 (Ironized-lentivirus) 38
3-3-2 磁性慢病毒載體 (Ironized-lentivirus)接合表現 39
3-4 磁性慢病毒載體之表面特徵 40
3-5 四氧化三鐵接合慢病毒載體之物性檢測 41
3-6 四氧化三鐵接合慢病毒載體之最佳化條件 42
3-7 四氧化三鐵接合Lentivirus局部磁吸病毒定位之抗體染色 44
3-8 四氧化三鐵接合Lentivirus磁控定位之細胞 45
3-9 使用攜帶有功能性shRNA-Lentivirus載體觀察細胞凋亡之能力 47
3-10 攜帶功能性shRNA-慢病毒載體細胞凋亡之能力 48
3-11外部磁場輔助磁性shRNA-慢病毒載體 (Ironized shRNA-lentivirus)促使細胞凋亡之表現 49
3-11-1 局部定位磁性shRNA-慢病毒載體 TUNEL 染色之表現 49
3-11-2 局部定位磁性shRNA-慢病毒載體以活細胞與死細胞染色之檢測 52
第四章 結論 54
第五章 參考文獻 55


圖目錄
圖 1-1 基因治療之多元化應用 3
圖 1-2 體外和體內用於基因治療之策略 4
圖 1-4 基因傳遞中主要之物理方法 6
圖 1-5 使用腺病毒作為基因治療載體 7
圖 1-6 當前於癌症之臨床試驗中所使用不同類型之溶瘤病毒及治療方式 9
圖 1-7 溶瘤病毒使用之範例以及直接注射病毒載體之遞送系統,病毒載體 (綠色圓圈)直接定位注射到腦組織中(標的細胞) 9
圖 1-8 慢病毒轉染之示意圖 11
圖 1-9 慢病毒之生產過程 12
圖 1-10 在生物體內RNA沉默基因之途徑 13
圖 1-11 利用慢病毒載體攜帶有SHRNA基因,轉導抗HIV基因到愛滋病患者之造血幹細胞進行治療 15
圖 1-12 奈米氧化鐵與不同的生物分子接合之示意圖 16
圖 1-13 磁性奈米粒子接合不同配體之示意圖 17
圖 1-14 接合磁性奈米粒子與6XHIS AAV/ NISTNP形成之複合物 17
圖 1-15 生物性接合磁性奈米粒子,透過在帶有磁場引導下在細胞質中產生定位,進一步觀察空間和時間的生物訊號 18
圖 1-16 實驗流程圖 19
圖 1-17 磁性奈米氧化鐵結合慢病毒 (LENTIVIRUS) 之示意圖 20
圖 2-1 實驗純化流程 26
圖 2-2 病毒純化機 26
圖 2-3 純化濃縮慢病毒載體示意圖及病毒載體感染細胞之表現 28
圖 2-4 四氧化三鐵接合慢病毒載體之鍵結方式 28
圖 2-5 磁鐵吸附位置與SHAKER搖晃模擬示意圖 31
圖 2-6 磁性 SHRNA-慢病毒載體誘導細胞凋亡之示意圖 33
圖 3-1 構築慢病毒載體 (LENTIVIRUS) 之質體系統 35
圖 3-2 構築LENTIVIURS 之DNA瓊脂凝膠圖 36
圖 3-3 純化後LENTIVIRUS感染細胞之螢光表現 38
圖 3-4 透過EDC與NHS作用將四氧化三鐵接合LENTIVIRUS之流程圖 38
圖 3-5 EDC、NHS活化四氧化三鐵與慢病毒載體接合形成載體之情形 39
圖 3-6 以穿透式顯微鏡觀察四氧化三鐵接合慢病毒載體之表面特徵 41
圖 3-7 四氧化三鐵接合LENTIVIRUS載體毒性測試 42
圖 3-8 磁性慢病毒載體合成比例最佳化之定性與定量表現 44
圖 3-9 磁性慢病毒載體磁吸定位之抗體螢光表現 45
圖 3-10 磁性慢病毒載體磁吸定位之螢光表現 47
圖 3-11 SHRNA-EGFR慢病毒載體之WESTERN BLOTTING分析 48
圖 3-12 SHRNA-慢病毒載體之細胞毒性測試 49
圖 3-13 以TUNEL染色觀察四氧化三鐵接合SHRNA-慢病毒載體操控定位之細胞凋亡表現 52
圖 3-14 以LIVE AND DEAD染色觀察四氧化三鐵接合SHRNA-慢病毒載體遙控定位之應用 53
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