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研究生： 鄭宏足
Cheng, Hung Tsu
論文名稱： 用基因表現圖譜分辨傳統中醫的四逆湯證
The Classification of Sini Decoction Pattern in Traditional Chinese Medicine by Gene Expression Profiling
指導教授： 許志楧
Hsu, Ian C
口試委員: 林昭庚
Lin, Jaung Geng
黃怡超
Huang, Y.-T.
傅建中
Fu, Chien Chung
施純全
Shih,Chun Chuan
學位類別： 博士
Doctor
系所名稱： 工學院 - 奈米工程與微系統研究所
Institute of NanoEngineering and MicroSystems
論文出版年： 2016
畢業學年度： 104
語文別： 中文
論文頁數： 148
中文關鍵詞： 四逆湯證 、傳統中醫 、證 、基因表現圖譜 、基因微陣列晶片 、生物標記基因
外文關鍵詞： Sini decoction pattern (SDP), traditional Chinese medicine (TCM), ZHENG, cDNA microarray, gene expression profiling, biomarkers
相關次數： 點閱：2  下載：0 
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    • ｢四逆湯證｣是傳統中醫在臨床上常被診斷出來的證型，我們依據《傷寒雜病論》
    的描述來設計問卷，請中醫師們協助評分，得到兩組症狀：｢脈沉微欲絕｣與｢四肢厥冷｣，作為專家共識的四逆湯證診斷標準。接著，以此診斷標準收集了 24 位患者的血液樣本，進行兩個迴圈 48 片的基因微陣列晶片雜合實驗。其中 6 個四逆湯證及 6 個非四逆湯證的樣本作為｢迴圈一」訓練組，用訓練組的基因表現圖譜，來尋找四逆湯證的生物標記基因。另外的 6 個四逆湯證及 6 個非四逆湯證的樣本則作為｢迴圈二｣測試組，在測試組中，將這些生物標記基因的表現圖譜進行相同條件的階層分群，可以成功的將測試組的 12 個樣本區分出四逆湯證群與非四逆湯證群。研究成果顯示，生物標記基因的表現圖譜，可以強化傳統中醫證型的科學化診斷，提供傳統中醫在現代分子生物學領域裡新的風貌與詮釋。

    We investigated the syndromes of the Sini decoction pattern (SDP). To obtain a
    common profile for SDP, we distributed questionnaires to 300 clinical traditional Chinese
    medicine practitioners. According to the survey, we concluded 2 sets of symptoms for SDP:
    (1) pulse feels deep or faint and (2) reversal cold of the extremities. Then we collected 24 individuals, and extracted their total mRNA of peripheral blood mononuclear cells for cDNA microarray experiments. 12 samples were used as the training set to identify the biomarkers for distinguishing the SDP and non-SDP groups. The remaining 12 samples were used as the test set. The test results indicated that the gene expression profiles of the
    identified biomarkers could effectively distinguish the 2 groups.

    目錄 第一章 引言 .............................................................................................................. - 1 - 第二章 研究動機 ...................................................................................................... - 9 - 第三章 材料與方法 ................................................................................................ - 11 - 第一節 選擇證型 ........................................................................................... - 11 - 第二節 設計及寄發問卷 ............................................................................... - 12 - 一、 設計問卷 ........................................................................................... - 12 - 二、 寄發問卷 ........................................................................................... - 12 - 第三節 設計實驗模式 ................................................................................... - 13 - 第四節 收集樣本 ........................................................................................... - 13 - 第五節 分離 PBMC、運送及保存、萃取 total RNA ................................... - 14 - 一、 分離 PBMC ....................................................................................... - 14 - 二、 運送及保存 ....................................................................................... - 15 - 三、 萃取 total RNA .................................................................................. - 15 - 第六節 點印基因微陣列晶片 ........................................................................ - 16 - 第七節 基因微陣列晶片雜合反應 ................................................................ - 18 - 第八節 統計分析資料與尋找生物標記基因................................................. - 19 - 一、 影像分析 ........................................................................................... - 19 - 二、 資訊前處理（PreProcessing）.......................................................... - 22 - 三、 正規化方法（Normalization） ......................................................... - 23 - 四、 檢定假說（Hypothesis Testing） ...................................................... - 24 - 第九節 群集分析和預測能力分析 ................................................................ - 24 - 第十節 實驗確認 ...........................................................................................- 25 - 第十一節 功能性註解和富集分析 ....................................................................- 26 - 第四章 結果 ............................................................................................................ - 27 - 第一節 問卷結果 ...........................................................................................- 27 - 第二節 收集樣本、進行基因微陣列晶片雜合反應 ......................................- 27 - 第三節 由訓練組尋找生物標記基因 .............................................................- 30 - 第四節 在測試組中將樣本分群 ....................................................................- 33 - 第五節 功能性註解及富集分析 ....................................................................- 34 - 第五章 討論 ............................................................................................................ - 37 - 第一節 《傷寒雜病論》中四逆湯證的原文探義 .........................................- 37 - 第二節 問卷結果的分析 ................................................................................- 41 - 第三節 收集樣本的過程 ................................................................................- 42 - 第四節 樣本的保存條件 ................................................................................- 43 - 一、 血液樣本的保存對分離 PBMC 品質的影響.....................................- 43 - 二、 PBMC 的保存對萃取 RNA 品質的影響 ...........................................- 44 - 第五節 α-、及 β- globin mRNA 的干擾 ........................................................- 49 - 第六節 「迴圈二」（測試組）未成功分群的樣本........................................- 51 - 第七節 基因本體名詞與四逆湯證原文的關係 .............................................- 52 - 第八節 微陣列晶片數據和 qPCR 數據之間的相關性確認...........................- 52 - 一、 基因微陣列晶片數據和 qPCR 數據之間的相關性確認（二重複） - 53 - 二、 基因微陣列晶片數據和 qPCR 數據之間的相關性確認（三重複） - 54 - 第六章 結論與未來展望 ........................................................................................ - 57 - 參考文獻 .................................................................................................................... - 58 - 附錄一 附件 1~19 ................................................................................................... - 65 - 附件 1 「四逆湯證診斷標準」方證研究專家問卷 ........................................ - 65 - 附件 2 中醫四診辨證表 .................................................................................. - 69 - 附件 3 受試者同意書 ...................................................................................... - 71 - 附件 4 基因重組實驗暨人體相關實驗申請同意書 ........................................ - 74 - 附件 5 Apptication for Approval of Human Subjects Research ......................... - 75 - 附件 6 以 Ficoll-Paque PREMIUM 分離 PBMC 的操作步驟 ......................... - 78 - 附件 7 以 RNeasy Mini Kit 萃取 RNA 的操作步驟 ........................................ - 83 - 附件 8 以 GLOBINClear 去除 m-RNA 的操作步驟 ....................................... - 87 - 附件 9 Agilent RNA 6000 Nano Assay Protocol ............................................... - 94 - 附件 10 Guidelines for Using the Controls Provided ........................................ - 95 - 附件 11 Procedure of 3DNA Array 900 Kit Labeling ........................................ - 97 - 附件 12 Hybridization of DNA Microarrays ................................................... - 102 - 附件 13 「迴圈一」不同篩選條件下的所有組合 ........................................ - 106 - 附件 14 「四逆湯證診斷標準」方證研究專家問卷回收結果 ..................... - 109 - 附件 15 192 個生物標記基因的富集分析以及基因本體名詞...................... - 111 - 附件 16 122 位受試者證型症狀列表 ............................................................ - 115 - 附件 17 122 位受試者生化檢查報告 ............................................................ - 129 - 附件 18 移除α-與β- globin mRNA 干擾因子前後基因表現比較 ............. - 139 - 附件 19 基因微陣列晶片數據和 qPCR 數據之間的相關性確認 ................. - 140 - 附錄二 發表在Evidence-Based Complementary and Alternative Medicine 的複印本 圖目錄 圖 1 「迴圈一」（訓練組）和「迴圈二」（測試組）的實驗設計......................... - 14 - 圖 2 本實驗室自製之自動化機械手臂基因微陣列晶片點印系統......................... - 17 - 圖 3 每一片基因微陣列晶片可點印之總點數為 26*26*48=32448 點................... - 17 - 圖 4 晶片螢光掃描儀 Virtek ChipReader 擷取每個基因的螢光影像圖 ................. - 19 - 圖 5 以 GenePix Pre 5.0 進行圈點 ......................................................................... - 20 - 圖 6 每一個擷取的螢光點座標、紅綠光訊號強度、比值以及個自背景值 ......... - 20 - 圖 7 螢光擷取後每一區塊圈點的情形 ................................................................... - 21 - 圖 8 依據篩選點原則剔除或計算所擷取的螢光點 ................................................ - 21 - 圖 9 三種經篩選點原則剔除的點(absent spot, undetected spot and bad spot) ........ - 21 - 圖 10 經 GenePix Pro 的軟體程式計算基因微陣列晶片螢光影像後的資料結果 - 22 - 圖 11 「四逆湯證診斷標準」方證研究專家問卷統計結果 .................................. - 28 - 圖 12 確認樣本內 total RNA 的品質 ...................................................................... - 29 - 圖 13 「迴圈一」（訓練組）的 12 個樣本進行階層分群的結果 .......................... - 31 - 圖 14 迴圈二的 12 個樣本進行階層分群的結果 ................................................... - 34 - 圖 15 採取血液樣本後立即分離的 PBMC 顯微鏡下所顯示 ................................. - 43 - 圖 16 血液樣本在冰箱中保存 2 小時後再分離的 PBMC 顯微鏡下所顯示 .......... - 43 - 圖 17 將取得的血液樣本，在 4℃冰箱中保存不同的時間後，分離 PBMC，萃取 RNA， 分別估算其 PBMC 細胞數與 RNA 濃度 ...................................................... - 45 - 圖 18 將取得的血液樣本，在 4℃冰箱中保存不同的時間後，分離 PBMC 並在液態 氮桶保存 7 天後，萃取 RNA，分別估算其 PBMC 細胞數與 RNA 濃度 .. - 45 - 圖 19 將取得的血液樣本，立即分離 PBMC，並在液態氮桶保存不同時間後，萃取 RNA，分別估算其 PBMC 細胞數與 RNA 濃度 ..........................................- 45 - 圖 20 移除「迴圈一」樣本中 α-與β- globin mRNA 前後有效點數的比較 .........- 50 - 圖 21 移除「迴圈一」樣本中 α-與β- globin mRNA 前後控制組點數的比較 .....- 50 - 表目錄 表 1 192 個生物標記基因 ....................................................................................... - 32 - 表 2 由 192 個生物標記基因挑選出的 11 個基因本體名詞（依 P 值排序） ....... - 35 - 表 3 傷寒學派 13 份統計結果 ................................................................................ - 41 - 表 4 非傷寒學派 29 份統計結果 ............................................................................ - 41 - 表 5 全部 42 份有效問卷統計結果 ......................................................................... 41 表 6 不同保存條件下 PBMC 數量和 RNA 純度分析 ............................................ - 44 - 表 7 不同保存條件下 RNA 完整性分析 ................................................................ - 46 - 表 8 作為 qPCR 確認標的 10 個基因 ..................................................................... - 53 -

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