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系統識別號 U0007-2906201109550400
論文名稱(中文) 馬兜鈴酸誘導小鼠腎炎中蛋白質體之螢光高效能液相層析串聯質譜分析
論文名稱(英文) Proteome analysis of aristolochic acid nephropathy in mouse kidney by fluorogenic derivatization-liquid chromatography-tandem mass spectrometry method
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 99
學期 2
出版年 100
研究生(中文) 張文歆
研究生(英文) Wen-Shin Chang
學號 M301098029
學位類別 碩士
語文別 中文
口試日期 2011-06-16
論文頁數 126頁
口試委員 委員-蔡東湖 教授
委員-李仁愛 副教授
指導教授-陳世銘 副教授
中文關鍵字 馬兜鈴酸腎病變  蛋白質體  螢光高效能液相層析串聯質譜 
英文關鍵字 Aristolochic acid nephropathy (AAN)  proteomics  fluorogenic derivatization-liquid chromatography-tandem mass spectrometry 
學科別分類
中文摘要 馬兜鈴酸腎病變 (aristolochic acid, AAN) 是一種快速進展到末期腎臟疾病的間質性腎炎,其原因是誤用含有馬兜鈴酸的生藥,而目前唯一的確診方式為腎臟組織切片。本研究利用蛋白質體分析方法,以鑑定在馬兜鈴酸腎病變後表現量改變的蛋白質,作為疾病特定的指標。利用投予AA飲用水 0.5 毫克/公斤 體重/天 ,誘導6週齡雄性C3H/He小鼠8週,於誘導後8週、10週及12週不同時間點分別犧牲。取得腎臟組織經均質後,利用螢光衍生化試劑DAABD-Cl與其反應,以螢光高效能液相層析儀 (FD-HPLC) 分離並定量,收集表現量有差異的蛋白質以液相層析串聯質譜儀 (LC-MS/MS) 與Mascot數據庫檢索系統定性。實驗結果顯示,誘導8週後,AA組小鼠的血糖值、血中尿素氮、尿蛋白及尿中N-acetyl-β-D-glucosaminidase (NAG) 均有上升;腎組織鏡檢發現腎小管萎縮、間質細胞浸潤及纖維化。在誘導後8週、10週及12週的AA組小鼠,與正常組小鼠比較,分別有16、54、24根波峰有顯著的差異 (p < 0.05),蛋白質經鑑定為與抗氧化、細胞外基質蛋白質與其相關訊息路徑、發炎、細胞凋亡及ATP合成有關。本研究結果將有助於找到馬兜鈴酸腎病變的生物標誌,以應用至早期診斷,並更加了解馬兜鈴酸腎病變的病理機轉。
英文摘要 Aristolochic acid nephropathy (AAN) is a progressive interstitial nephritis which rapidly leading to end-stage renal disease. The reason is that people misuse the herb containing AA. So far, using kidney biopsy is the only way to diagnose. Therefore, this study was designed to establish a new method of proteomics to identify the differential expression of proteins in AAN in order to find out the specific indicators of AAN. The 6 week-old male C3H/He mice were treated with AA (0.5 mg/kg/day) for 8 weeks. The mice were sacrificed at 8, 10 and 12 weeks since the treatment began. The homogenate of the kidney was derivatized with DAABD-Cl. The dirivatized proteins were separated and quantified by high performance liquid chromatography with fluorescence detection (FD-HPLC). The differential proteins were identified by liquid chromatography tandem mass spectrometry (LC-MS/MS) with MASCOT database searching system. After 8 weeks of AA administration, they were showed renal injury by increasing blood glucose, blood urea nitrogen (BUN), urine protein and N-acetyl-β-D-glucosaminidase (NAG). In addition, tubular atrophy, interstitial infiltration and fibrosis were found in histopathology. The significantly altered expression between the normal and AA group at 8, 10 and 12 weeks were 16, 54 and 24 peaks, respectively. Those proteins were identified as anti-oxidant, extracellular matrix related, inflammatory, apoptotic and in ATP synthesis. This protein profile may serve to find new biomarkers to improve early detection and realize more the mechanism of AAN.
論文目次 目錄 ....................................................................................... i
圖目錄 ....................................................................................... iv
表目錄 ....................................................................................... vii
縮寫表 ....................................................................................... viii
中文摘要 ....................................................................................... xii
英文摘要 ....................................................................................... xiii
第一章 緒言 ....................................................................................... 1
第二章 文獻回顧................................................................................. 2
第一節 馬兜鈴酸腎病變的由來................................................... 2
第二節 馬兜鈴酸之基本特性....................................................... 3
2-1 用途................................................................................... 3
2-2 含馬兜鈴酸的生藥及使用現況....................................... 3
2-3 結構與生理特性............................................................... 4
2-4 馬兜鈴酸的代謝............................................................... 5
第三節 馬兜鈴酸腎病變 (Aristolochic acid nephropathy, AAN) 10
3-1 臨床表現及病理特徵....................................................... 10
3-2 致病機轉........................................................................... 11
3-3 藥物治療........................................................................... 12
第四節 馬兜鈴酸腎病變的實驗模型........................................... 13
4-1 馬兜鈴酸的慢性腎毒性................................................... 13
第五節 腎小管間質性纖維化....................................................... 14
5-1 TGF-β................................................................................ 19

第六節 蛋白質體學 (Proteomics)................................................ 23
6-1 定義................................................................................... 23
6-2 蛋白質體方法學............................................................... 24
6-3 腎臟疾病生物標記的發現............................................... 27
6-4 螢光衍生化試劑於蛋白質體的應用............................... 28
第三章 研究目的................................................................................. 30
第四章 材料與方法............................................................................. 31
第一節 實驗試藥、耗材與儀器................................................... 31
1-1 實驗試藥........................................................................... 31
1-2 耗材與儀器....................................................................... 32
第二節 實驗動物........................................................................... 33
第三節 實驗方法........................................................................... 33
3-1 動物飼養流程................................................................... 33
3-2 尿液收集........................................................................... 34
3-3 腎臟組織均質液............................................................... 35
3-4 小鼠腎臟均質液之蛋白質定量....................................... 35
3-5 螢光衍生化條件............................................................... 36
3-6 蛋白質分離....................................................................... 38
3-7 小鼠腎臟組織之蛋白質定性........................................... 39
3-7.1 蛋白質消化............................................................. 39
3-7.2 LC-MS/MS分析..................................................... 39
3-7.3 MASCOT 結果比對............................................... 43
3-8 統計分析方法................................................................... 44
第五章 結果......................................................................................... 46
第一節 小鼠之生化值測定結果................................................... 46
1-1 尿蛋白、NAG含量分析................................................. 46
1-2 血清中BUN及血糖之測定.......................................... 49
第二節 小鼠的腎臟細胞型態....................................................... 50
第三節 蛋白質體實驗................................................................... 52
3-1 FD-HPLC條件................................................................. 52
3-2 衍生化試劑的溶劑選擇................................................... 55
3-3 統計結果........................................................................... 58
3-4 蛋白質定性結果............................................................... 63
第六章 討論......................................................................................... 71
第一節 誘導AAN小鼠模型之腎臟損傷情形............................ 71
第二節 研究結果與AAN蛋白質體學研究文獻之比較............ 72
第三節 定性蛋白質與腎臟疾病之關係....................................... 76
3-1 抗氧化 (anti-oxidation) 相關.......................................... 76
3-2 細胞外基質ECM相關及其下游傳訊路徑.................... 80
3-3 Wnt/β-catenin訊息傳遞路徑........................................... 97
3-4 發炎相關因子................................................................... 98
3-5 細胞凋亡 (apoptosis) ...................................................... 104
3-6 癌症發生因子 (oncogenetics related factors) ................ 106
3-7 ATP合成 (ATP synthesis) .............................................. 109
3-8 代謝相關 (metabolism)................................................... 110
3-9 其他 (others).................................................................... 111
第四節 推測AAN小鼠腎臟的生物標記.................................... 111
第七章 結論與未來展望..................................................................... 112
參考文獻................................................................................................ 114
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