臺灣博碩士論文加值系統

本研究以蛋白質體分析方法，探討去氫羥化腎上腺皮質素 (prednisolone) 對於馬兜鈴酸 (aristolochic acid, AA) 腎病變小鼠在治療上的可能機轉。實驗期間為10週，選用雄性C3H/He小鼠，分normal組、AA組以及prednisolone組進行試驗。於實驗前八週，AA組及prednisolone組投予AA飲用水0.5 mg/kg/day，最後兩周AA組和prednisolone組分別投予蒸餾水及prednisolone 2 mg/kg/day；normal組於實驗期間全程給予蒸餾水。實驗結束後將小鼠腎臟組織均質化，利用螢光衍生化試劑DAABD-Cl (4-[2-(Dimethylamino) ethylaminosulfonyl]-7-chloro-2,1,3-benzoxadiazole) 衍生化，再以螢光高效能液相層析儀 (FD-HPLC) 分離，收集表現量具統計差異的波峰，利用液相層析串聯質譜儀 (LC-MS/MS) 及MASCOT資料庫進行定性和蛋白質鑑定。
經比對分析後，發現39個和馬兜鈴酸腎病變相關的蛋白質，針對其中12個與細胞ATP合成及抗氧化路徑相關蛋白作探討，可分為：糖解作用、抗氧化作用及ATP合成作用。其中大部分與糖解作用及ATP合成相關的蛋白質在prednisolone組的表現量相較於AA組都有顯著降低的趨勢。而抗氧化蛋白在prednisolone組的表現量相較於AA組則有顯著增加的情形。由實驗結果推論，藉由prednisolone的抗發炎效果，可減少腎組織糖解作用進行、ATP消耗以及降低氧化壓力來延緩馬兜鈴酸腎病變的進展。

This study was designed to investigate the effects and mechanism of prednisolone treatment in aristolochic acid nephropathy (AAN) mice by proteomics analysis. The male C3H/He mice were separated into normal, AA and prednisolone group and the experimental period was 10 weeks. Both AA group and prednisolone group were treated with AA (0.5 mg/kg/day) for 8 weeks. For the next two weeks, AA group was treated with distilled water while the treatment group was treated with prednisolone (2 mg/kg/day). The normal group was administered distilled water for 10 weeks without AA. The homogenate of the kidney was reacted with DAABD-Cl (4-[2-(Dimethylamino) ethylaminosulfonyl]-7-chloro-2,1,3-benzoxadiazole). The derivatized 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) using a MASCOT database searching system.
According to the results, there were 39 proteins associated with AAN. Focusing on ATP synthesis and anti-oxidation pathway, this study classified 12 of the 39 proteins into three categories: glycolysis, anti-oxidation, and ATP synthesis. Compared with AA group, most of the proteins related to glycolysis and ATP synthesis were significantly down-regulated in prednisolone group. On the other hand, proteins related to anti-oxidation were significantly up-regulated in prednisolone group comparing with AA group. These results indicate that prednisolone may slow the progression of AAN by decreasing glycolysis, ATP consumption and oxidative stress due to its known anti-inflammatory effect.

目錄 i
表目錄 iv
圖目錄 v
縮寫表 vii
中文摘要 x
Abstract xi
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馬兜鈴酸的用途 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 6
第三節 馬兜鈴酸腎病致病機轉 10
3-1 臨床表現與病理特徵 10
3-2 致病機轉 12
3-3 腎小管間質性纖維化 13
3-3-1 TGF-β 19
3-4 致癌機轉 23
3-5 藥物治療 24
第四節 Prednisolone 25
第五節 蛋白質體學 31
5-1 定義 31
5-2 螢光衍生化試劑於蛋白質體的應用 32
第三章 研究目的 34
第四章 材料與方法 35
第一節 實驗試藥、耗材與儀器 35
1-1實驗試藥 35
1-2耗材與儀器 36
第二節 實驗動物 37
第三節 實驗方法 38
3-1 動物飼養流程 38
3-2 腎臟組織均質液 39
3-3 小鼠腎臟均質液之蛋白質定量 39
3-4 螢光衍生化條件 40
3-5 HPLC分離條件 42
3-6 小鼠腎臟組織之蛋白質定性 43
3-6-1 蛋白質消化 43
3-6-2 LC-MS/MS 分析 43
3-6-3 MASCOT 數據庫比對 44
3-7 統計分析方法 45
第五章 結果 46
第一節 差異波峰比對 46
第二節 蛋白質定性結果 49
第三節 腎病變機轉相關蛋白表現情形 52
3-1 糖解作用相關蛋白 54
3-2 抗氧化相關蛋白 57
3-3 ATP 合成相關蛋白 58
第六章 討論 60
定性蛋白質與腎臟疾病之關係 60
1-1糖解作用 61
1-2抗氧化作用 67
1-3 ATP 合成 70
第七章、結論 73
參考文獻 75

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