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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18043完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 何佳安(Ja-an Annie Ho),蕭寧馨(Ning-Sing Shaw) | |
| dc.contributor.author | Yu-Ning Chang | en |
| dc.contributor.author | 張祐寧 | zh_TW |
| dc.date.accessioned | 2021-06-08T00:49:25Z | - |
| dc.date.copyright | 2020-09-17 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-08-18 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18043 | - |
| dc.description.abstract | 食道癌具有隱形殺手之稱，近十年來蟬聯國人十大癌症死因之一。早期食道癌並無任何症狀，且診斷方式多以侵入式為主，導致國人檢查之意願大幅降低，也因此錯過黃金治療期。根據研究顯示，血液中的miR-365、miR-22可作為早期食道癌之生物標記。由此，我們利用循環鏈置換放大策略 (Circular Strand Displacement Amplification, CSDA)結合三螺旋DNA奈米開關 (Triplex DNA nanoswitch)，開發不須酵素參與且恆溫之電化學核酸感測平台，作為一種非侵入式之早期食道癌診斷工具。miR-365及miR-22具有啟動循環鏈置換放大反應之功能，我們透過膠體電泳分析發現在1小時即有足夠大量的單股觸發子 (Triplex reporter, TR) 被生成釋出，達到有效循環放大之成效。此外，我們透過反向平行三螺旋核酸結構 (Antiparallel triplex) 之設計，能有效降低非專ㄧ性的雜訊，藉此提升反應之訊噪比。接著，被釋出之兩種TR分別可與修飾在電極表面之核酸探針 (Capture probe, CP) 形成60% TAT及80% TAT之平行三螺旋核酸結構 (Parallel triplex)。由miR-365主導之60% TAT三螺旋核酸只能於酸性環境下穩定生成，而miR-22所主導之80% TAT三螺旋核酸則可於酸性至中性環境下穩定形成。透過pH值調控可於3分鐘內使核酸探針折彎，與TR穩定形成三螺旋核酸結構，促使核酸探針末端修飾之甲基藍分子 (Methylene blue, MB) 靠近電極表面而產生更高的電化學訊號。本研究利用反應液pH的調控作為平台的開關，在平台上只需標定一種電化學活性分子，透過不同的pH值調控Triplex nanoswitch構型改變便能雙重偵測不同的目標待測物。經計算後miR-365、miR-22之偵測極限可分別下達6.2 pM及1.14 pM。此電化學偵檢平台具有快速、低成本、高靈敏性且具雙重偵測特性之優勢。我們相信其具有潛力被應用於食道癌或其他臨床疾病之檢測。 | zh_TW |
| dc.description.abstract | Esophageal cancer has been considered as the silent killer and ranked among the top ten leading causes of cancer death for more than a decade. Previous studies showed that circulating miR-365 and miR-22 were found to be potential biomarkers for early Esophageal cancer detection. Herein, we established an electrochemical platform with enzyme-free amplification that can be used as a non-invasive diagnostic tool for early-stage Esophageal cancer. Our detection scheme was initiated with a miR-365 and miR-22-induced circular strand replacement amplification (CSDA). It was followed by the production of a large number of triplex reporters (TR) in one hour that was confirmed by gel electrophoresis. We also found that anti-parallel triplex configuration of our probe design was able to reduce the non-specific hybridization significantly. Subsequently two different releasing TR hybridized with methylene blue (MB)-sensitized CP (MB-CP) modified on the electrode to form 60% TAT parallel triplex and 80% TAT parallel triplex, respectively. The formation of 60% TAT triplex triggered by miR-365 was found to yield steadily in an acidic environment only; however, the 80% TAT triplex controlled by miR-22 was generated in both acidic or neutral conditions. After the re-configuration of MB-CP to form triplex structure within three minutes, enabling MB to face toward the electrode that turned the signal-switch on. This newly developed biosensing platform is capable of detecting dual targets via pH control, offering the advantages of simplicity, cost effectiveness, and rapid detection. It holds great promise in diagnosis of liquid biopsy samples collected from EC patients, and sheds new light on the development of point-of-care (POC) diagnostics. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T00:49:25Z (GMT). No. of bitstreams: 1 U0001-1308202016033900.pdf: 5497807 bytes, checksum: 3d1271196b05a2bcfa4e26376434724c (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | 謝辭.............................................................................................................................................i 中文摘要....................................................................................................................................ii ABSTRACT............................................................................................................................ iii 縮寫表.......................................................................................................................................iv 目錄............................................................................................................................................v 圖目錄........................................................................................................................................x 表目錄.................................................................................................................................... xiii 第 1 章 緒論....................................................................................................................1 第 2 章 文獻回顧............................................................................................................3 2.1 食道癌 (Esophageal cancer)......................................................................................3 2.1.1 認識食道及食道癌..........................................................................................3 2.1.2 食道癌現況......................................................................................................5 2.1.3 食道癌之成因與症狀......................................................................................6 2.1.4 食道癌診斷與治療..........................................................................................6 2.2 微型核醣核酸 (MicroRNA)......................................................................................8 2.2.1 MicroRNA 簡介 ...............................................................................................8 2.2.2 生合成與作用機制...........................................................................................8 2.2.3 microRNA 與癌症............................................................................................9 2.2.4 microRNA 作為食道癌之生物指標..............................................................10 2.2.5 microRNA 傳統偵測方式..............................................................................12 2.3 等溫核酸放大技術 (Isothermal amplification) .............................................13 2.3.1 等溫核酸放大技術簡介................................................................................13 2.3.2 催化髮夾組裝反應 (Catalytic hairpin assembly, CHA)..............................14 2.3.3 循環鏈置換放大反應(Circular strand displacement amplification, CSDA) 15 2.4 核酸生物感測器 (Nucleic acid biosensor) ....................................................17 2.4.1 生化感測器簡介與應用..........................................................................17 2.4.2 電化學生化感測器..................................................................................18 2.5 三螺旋核酸 (Triplex DNA)......................................................................................21 2.5.1 三螺旋核酸結構............................................................................................21 2.5.2 三螺旋核酸特性............................................................................................22 2.5.3 三螺旋核酸應用於電化學生化感測器........................................................24 2.6 電化學分析法 (Electrochemical detection) ............................................................25 2.6.1 三電極系統....................................................................................................25 2.6.2 電化學分析法.................................................................................................26 第 3 章 研究設計..........................................................................................................29 第 4 章 實驗材料與方法..............................................................................................34 4.1 實驗儀器..........................................................................................................34 4.2 實驗材料...................................................................................................................35 4.2.1 核酸序列........................................................................................................35 4.2.2 藥品與試劑....................................................................................................38 4.2.3 緩衝溶液........................................................................................................39 4.3 循環鏈置換放大反應 (CSDA) ...............................................................................40 4.3.1 聚丙烯醯胺膠體電泳 (Polyacrylamide gel electrophoresis, PAGE)...........40 4.3.2 CSDA-1 系統之可行性及 Fuel strand (F) 長度優化...................................40 4.3.3 CSDA-1 系統之 probe 的 CG 位置之優化...................................................40 4.3.4 CSDA-1 系統中 antiparallel triplex 構型降低非專一性反應之探討..........41 4.3.5 CSDA-1 系統之反應緩衝溶液 MgCl2 濃度最佳化 .....................................41 4.3.6 CSDA-1 系統之反應溫度最佳化..................................................................41 4.3.7 CSDA-1 系統之反應時間最佳化..................................................................41 vii 4.3.8 CSDA-1 系統之 F/Te 比例最佳化 ...............................................................42 4.3.9 CSDA-2 系統之可行性測試..........................................................................42 4.3.10 CSDA-2 系統中 Triplex reporter (TR) 長度對產物釋放效率之探討 ......42 4.3.11 CSDA-1、CSDA-2 系統之專一性測試......................................................42 4.3.12 CSDA-1、CSDA-2 系統對於目標 miRNA 之放大能力測試...................43 4.3.13 Double-output 循環放大設計對於 CSDA-1、CSDA-2 系統之放大效能鑑 定..............................................................................................................................43 4.4 三螺旋核酸構型可行性之分析...............................................................................43 4.4.1 熔解曲線(melting curve)分析.......................................................................43 4.4.2 化合物黃連素 Berberine 之螢光測定..........................................................44 4.4.3 延長及雙股序列長度對 CSDA-1 產物形成 60% TAT 三螺旋核酸生成影 響之探討..................................................................................................................44 4.4.4 Link 長度對 60% TAT 三螺旋核酸生成影響之探討...................................44 4.4.5 TAT 比例之最佳化.........................................................................................45 4.4.6 CSDA-2 產物形成 80% TAT 三螺旋核酸之可行性測試 ............................45 4.4.7 延長及雙股序列長度對 80% TAT 三螺旋核酸生成影響之探討 ...............45 4.4.8 Triplex 長度最佳化........................................................................................45 4.5 電化學分析平台.......................................................................................................46 4.5.1 工作電極表面鑑定........................................................................................46 4.5.2 EC platform-1 之溶液 pH 值最佳化 .............................................................48 4.5.3 EC platform-1 之 Triplex repoeter (TR) 反應時間最佳化...........................48 4.5.4 EC platform-1 之頻率設定最佳化 ................................................................49 4.5.5 EC platform-1 之偵測溶液最適化 ................................................................49 4.5.6 EC platform-1 之阻隔劑 (blocking agent) 種類最適化..............................49 4.5.7 EC platform-1 之核酸探針(capture probe)濃度最佳化................................50 4.5.8 EC platform-1 之阻隔劑 (blocking agent) 濃度最佳化..............................50 4.5.9 不同 pH 對 EC platform-2 訊號影響之探討 ...............................................51 4.5.10 不同溶液對 EC platform-2 訊號影響之探討 ............................................51 4.5.11 Electrochemical platform-1、Electrochemical platform-2 靈敏性測試 .....51 第 5 章 實驗結果與討論..............................................................................................53 5.1 循環鏈置換放大反應(CSDA) ..................................................................................53 5.1.1 CSDA-1 系統之可行性及 Fuel strand (F) 長度優化...................................53 5.1.2 CSDA-1 系統之 probe 的 CG 位置之優化...................................................57 5.1.3 CSDA-1 系統中 antiparallel triplex 構型降低非專一性反應之探討..........59 5.1.4 CSDA-1 系統之反應緩衝溶液 MgCl2 濃度最佳化 .....................................62 5.1.5 CSDA-1 系統之反應溫度最佳化..................................................................62 5.1.6 CSDA-1 系統之反應時間最佳化..................................................................62 5.1.7 CSDA-1 系統之 F/Te 比例最佳化 ...............................................................63 5.1.8 CSDA-2 系統之可行性測試..........................................................................68 5.1.9 CSDA-2 系統中 Triplex reporter (TR) 長度對產物釋放效率之探討 ........70 5.1.10 CSDA-1、CSDA-2 系統之專一性測試.................................................73 5.1.11 CSDA-1、CSDA-2 系統對於目標 miRNA 之放大能力測試..............77 5.1.12 Double-output 循環放大設計對於 CSDA-1、CSDA-2 系統之放大效能鑑 定..............................................................................................................................77 5.2 三螺旋核酸構型可行性之分析......................................................................80 5.2.1 延長及雙股序列長度對 CSDA-1 產物形成 60% TAT 三螺旋核酸生成影 響之探討..................................................................................................................80 5.2.2 Link 長度對 60% TAT 三螺旋核酸生成影響之探討...................................85 5.2.3 TAT 比例之最佳化.........................................................................................91 5.2.4 CSDA-2 產物形成 80% TAT 三螺旋核酸之可行性測試 ............................95 5.2.5 延長及雙股序列長度對 80% TAT 三螺旋核酸生成影響之探討 ..............97 5.2.6 Triplex 長度最佳化......................................................................................100 5.3 電化學分析平台.....................................................................................................102 5.3.1 工作電極表面鑑定......................................................................................102 5.3.2 EC platform-1 之溶液 pH 值最佳化 ...........................................................103 5.3.3 EC platform-1 之 Triplex reporter (TR) 反應時間最佳化 .........................105 5.3.4 EC platform-1 之頻率設定最佳化 ..............................................................105 5.3.5 EC platform-1 之偵測溶液最適化 ..............................................................106 5.3.6 EC platform-1 之阻隔劑 (blocking agent) 種類最適化............................107 5.3.7 EC platform-1 之核酸探針 (Capture probe) 濃度最佳化.........................108 5.3.8 EC platform-1 之阻隔劑 (blocking agent) 濃度最佳化............................108 5.3.9 不同 pH 對 EC platform-2 訊號影響之探討 .............................................109 5.3.10 不同溶液對 EC platform-2 訊號影響之探討 ..........................................110 5.3.11 EC platform-1、EC platform-2 靈敏性測試 ............................................. 111 第 6 章 結論................................................................................................................113 第 7 章 參考文獻........................................................................................................114 | |
| dc.language.iso | zh-TW | |
| dc.title | 利用循環鏈置換策略結合三股螺旋 DNA 奈米開關開發對食道癌具特異性的微小核糖核酸之電化學感測平台 | zh_TW |
| dc.title | A Signal-on Electrochemical Biosensor for Esophageal Cancer-specific MicroRNAs Based on Triplex DNA Nanoswitch and Circular Strand Displacement Amplification | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 吳立真(Li-chen Wu),徐士蘭(Shih-Lan Hsu),周芳如(Fang Ru Jou),邢怡銘(I-ming HSING) | |
| dc.subject.keyword | 食道癌,微小核醣核酸,核酸等溫擴增技術,非酵素型核酸放大,循環鏈置換放大,三螺旋核酸,電化學感測器, | zh_TW |
| dc.subject.keyword | Esophageal cancer,microRNA,Enzyme-free nucleic acid amplification,isothermal amplification,Circular Strand Displacement Amplification,Triplex DNA nanoswitch,Electrochemical biosensor, | en |
| dc.relation.page | 120 | |
| dc.identifier.doi | 10.6342/NTU202003281 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2020-08-19 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科技學系 | zh_TW |
| 顯示於系所單位： | 生化科技學系 | |
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