本篇研究設計分子信籤(Molecular beacon，MB)探針，分別在5'和3'端以共價鍵連結螢光試劑和消光團，當加入分析物後，可誘導分子信籤的構型改變，並造成螢光訊號的差異，藉此應用於偵測肝素和篩選三聚體去氧核醣核酸結合物。
(一) 利用分子信籤為基礎的感測器來偵測人類血漿中的肝素：
肝素(Heparin)是一種具有多負電荷的葡萄糖胺多聚醣(Glycoaminoglycan)，在臨床上，常作為心血管手術的抗凝血劑，或者用於治療急性冠心症和預防靜脈血栓塞的發生。若是使用過量，可能造成出血或血小板減少等症狀，故需要一個準確且可靠的偵測方法，來密切監控其濃度變化就顯得相當重要。因此，本實驗去設計一個高選擇性、靈敏度且簡單快速的分子信籤來偵測肝素。分子信籤的Loop端含有22個鹼基，而Stem端含有12個腺嘌呤(Adenine, A )鹼基，並於5'和3'端分別修飾上螢光團(Carboxyfluorescein，FAM)和消光劑(4-(4-dimethyl-aminophenyl)diazenylbenzoic acid，DABCYL)，透過與Coralyne產生A2-coralyne-A2的反應，使分子信籤形成髮夾彎(Hairpin)結構，造成螢光試劑與消光劑相互碰撞，而螢光降低；當含有肝素時，可藉由靜電作用力將帶有正電荷的Coralyne置換出來，使分子信籤的髮夾彎結構被打開，造成螢光的恢復，利用此螢光回復值來對肝素進行定量，線性範圍為0.18 ~1.8 μg/mL，偵測極限值為60 ng/mL。此外，也可成功偵測人類血漿樣品中的肝素，並獲得其線性範圍為14.4 ~72 μg/mL ，偵測極限值為10 ng/mL。代表本感測器不僅具有高靈敏度、選擇性且可在複雜基質中成功偵測肝素。
(二) 設計分子信籤探針來篩選三聚體去氧核醣核酸結合物：
由於DNA經由轉錄、轉譯後會形成蛋白質，但若是DNA鹼基有突變發生，則可能造成蛋白質功能缺陷並造成疾病。因此，如果能在DNA轉錄過程中，將其與第三條寡核苷酸鏈結合，形成三股螺旋結構之DNA，就會抑制其轉錄過程，使疾病不會表現出來。但因為三股螺旋結構之DNA的磷酸骨架含有高負電荷，會使三股螺旋結構不易形成，故可藉由加入三聚體去氧核醣核酸結合物(Triplex DNA binders)，誘導並穩定三股螺旋DNA結構，故篩選Triplex DNA binders是一件重要的工作。因此本實驗設計分子信籤的Loop端含有15個鹼基，Stem端含有為8個胸腺嘧啶( Thymine, T )，並在5'和3'端分別修飾上螢光試劑(FAM)和消光劑(DABCYL)。由於Coralyne是個典型的Triplex DNA binders，故當分子信籤探針與去氧腺嘌呤寡核苷酸(Poly An)反應，並且加入Coralyne後，會使分子信籤的Stem端形成T=A˙T鹼基配對之三股螺旋結構，促使螢光試劑與消光團消互靠近，而造成螢光強度值下降，並透過探討Poly An序列的長度、濃度、緩衝溶液的鹽類濃度和pH值，可得到篩選Triplex DNA binders的最佳化條件。此外，利用圓二色光譜法和紫外光/可見光熔點實驗也成功證實其三股螺旋DNA結構的形成。最後將其應用於篩選可能成為Triplex DNA binders的結合物，並藉由其螢光淬息的程度，評估誘導和穩定三股螺旋結構的能力，從實驗結果得知除了Coralyne具有誘導形成三股螺旋結構的能力外，Sanguinarine也有作為Triplex DNA binders的潛力。因此，利用此螢光偵測的方式，即可簡易且快速地進行篩選。

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謝誌................................................................................................................................... i
摘要.................................................................................................................................. ii
目錄................................................................................................................................. iv
圖目錄............................................................................................................................ vii
表目錄........................................................................................................................... viii
縮寫表............................................................................................................................. ix
第一章、緒論.................................................................................................................. 1
一、前言.................................................................................................................. 1
1-1 核酸簡介.................................................................................................... 1
1-2 分子信籤簡介........................................................................................... 2
1-3 分子信籤的結構....................................................................................... 2
1-4 分子信籤的作用機制............................................................................... 3
1-5 分子信籤的熱變性研究........................................................................... 3
1-6 分子信籤的應用....................................................................................... 4
1-6-1 即時監控聚合酶鏈鎖反應 (Real-time PCR monitoring)............ 4
1-6-2 基因突變之檢測........................................................................... 4
1-6-3 研究DNA 與蛋白質之交互作用................................................. 5
1-6-4 活體細胞內RNA 的偵測............................................................. 5
1-6-5 應用於核酸生物感測器和DNA 晶片......................................... 6
1-7 新型的分子信籤....................................................................................... 6
二、研究動機.......................................................................................................... 7
第二章、利用分子信籤為基礎的感測器來偵測人類血漿中的肝素.......................... 8
一、前言.................................................................................................................. 8
二、實驗部分........................................................................................................ 11
v
2-1 實驗藥品................................................................................................. 11
2-2 儀器裝置.................................................................................................. 13
2-3 樣品配製方法......................................................................................... 14
2-4 實驗過程.................................................................................................. 15
三、結果與討論.................................................................................................... 16
3-1 感測機制的建立...................................................................................... 16
3-2 探討最佳化Coralyne 濃度和反應時間................................................ 17
3-3 探討形成髮夾彎結構之分子信籤的熔點............................................. 17
3-4 探討NaCl 濃度對形成髮夾彎結構之分子信籤的影響...................... 20
3-5 探討pH 值對形成髮夾彎結構之分子信籤的影響.............................. 20
3-5 髮夾彎結構之分子信籤應用於偵測肝素及反應時間的探討............. 23
3-6 肝素加入髮夾彎結構之分子信籤中對熔點之影響............................. 25
3-7 探討不同NaCl 濃度對偵測肝素之影響.............................................. 25
3-8 選擇性探討............................................................................................. 28
3-9 肝素的定量分析..................................................................................... 28
3-10 人類血漿樣品中肝素的定量分析....................................................... 32
四、結論................................................................................................................ 35
第三章、設計分子信籤探針來篩選三聚體去氧核醣核酸結合物............................ 37
一、前言................................................................................................................ 37
1-1 三股螺旋DNA 簡介.............................................................................. 37
1-2 三股螺旋DNA 結構.............................................................................. 37
1-3 三股螺旋DNA 的重要性...................................................................... 38
1-4 研究動機................................................................................................. 40
二、實驗部分........................................................................................................ 42
2-1 實驗藥品................................................................................................. 42
2-2 儀器裝置.................................................................................................. 45
vi
2-3 樣品配製方法......................................................................................... 46
2-4 實驗過程.................................................................................................. 47
三、結果與討論.................................................................................................... 48
3-1 感測機制的建立...................................................................................... 48
3-2 分子信籤應用於偵測Coralyne 以及熔點探討.................................... 49
3-3 以圓二色光譜法和紫外光-可見光熔點實驗偵測三股螺旋結構........ 51
3-3 探討Poly An 之長度................................................................................ 54
3-4 探討Poly A7 之濃度............................................................................... 54
3-5 探討NaCl 濃度之影響.......................................................................... 54
3-6 探討pH 值之影響.................................................................................. 58
3-7 篩選Triplex DNA binders...................................................................... 58
3-8 以分子信籤偵測Sanguinarine............................................................... 61
四、結論................................................................................................................ 67
第四章、參考文獻........................................................................................................ 68

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