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系統識別號 U0026-0812200914145630
論文名稱(中文) 結合穩定同位素二甲基標定及ClinProTools建立尿液蛋白質分析平台並應用於尋找良性前列腺肥大疾病的生物標記
論文名稱(英文) Urinary Proteomics by Combining Stable Isotope Dimethyl Labeling and ClinProTools for Biomarker Discovery Associated with Benign Prostatic Hyperplasia Disease
校院名稱 成功大學
系所名稱(中) 化學系碩博士班
系所名稱(英) Department of Chemistry
學年度 96
學期 2
出版年 97
研究生(中文) 歐秉原
研究生(英文) Bing-yuan Ou
學號 l3695401
學位類別 碩士
語文別 中文
論文頁數 95頁
口試委員 指導教授-陳淑慧
口試委員-周楠華
口試委員-周振陽
中文關鍵字 生物標記  良性前列腺肥大 
英文關鍵字 BPH  biomarker 
學科別分類
中文摘要 尿液是人體不需經過侵入性方法且容易收集到的檢體,所以被用來當作臨床診斷的一個理想的體液。此外,尿液中包含了相當豐富的生物標記來源,且可以對於像是腎臟、膀胱和泌尿道等各種疾病中的尿液蛋白質來得到潛在的生物標記。在本研究中,我們檢驗十六個正常人尿液樣品及十六個具有良性前列腺肥大的尿液樣品。並且結合以ClinProTools平台為基礎的MALDI-TOF MS和建立於LC-ESI-MS/MS的穩定同位素二甲基標定來尋找尿液裡的生物標記。我們首先使用以MALDI-TOF MS搭配ClinProTools為基礎,去找出在正常與疾病尿液之間明顯差異的胜肽質量。之後,利用穩定同位素二甲基標定在LC-ESI-MS/MS中去鑑定出尿液的蛋白質及胜肽並定出正常與疾病尿液之間的蛋白質的比例。相符合的胜肽及蛋白質質量被視為具有高度的潛力可用於早期診斷良性前列腺肥大的生物標記。藉由比較兩組的數據,我們可找到數個可信的生物標記,值得將來更進一步的研究。
英文摘要 Urine is a human body fluid that can be easily collected by non-invasive means, and thus is an ideal biospecimen for clinical diagnostics. Moreover, urine contains a rich sources of biomarkers with potential for human diseases, such as kidney, bladder and urinary tract diseases. In this study, we examined sixteen urine samples from healthy human and sixteen urine samples from patients with benign prostate hyperplasia(BPH). We coupled MALDI-TOF MS based ClinProTools platform with stable isotope dimethyl labeling based LC-ESI-MS/MS for biomarker discovery in the urines. MALDI-TOF MS based ClinProTools platform was first used to find out peptide masses which differ significantly between healthy and diseased urines. Then stable isotope dimethyl labeling based LC-ESI-MS/MS platform was applied to identify urine proteins/peptides and their corresponding ratios in healthy subjects relative to the diseased urines. The peptide/protein masses were shown to have potential as biomarkers for the detection of BPH. By comparing two sets of data, several markers were demonstrated to meet the criteria and thus deserve investigations.
論文目次 中文摘要.............................................. ....I
英文摘要..................................................II
誌 謝...................................................III
目 錄....................................................IV
表目錄...................................................VII
圖目錄..................................................VIII
第一章 序論...............................................1
第一節 蛋白質體發展歷程及質譜技術.........................1
1.1 蛋白質體學.............................................1
1.2 質譜儀技術.............................................2
1.3 質譜儀在蛋白質定量的應用..............................10
第二節 體液蛋白質體分析..................................11
2.1 尿液蛋白質體..........................................11
2.2 生物標記(Biomarker).................................13
2.3 找尋生物標記的方法....................................15
第三節 前列腺............................................16
3.1 前列腺的位置..........................................16
3.2 前列腺的功能..........................................17
3.3 前列腺的發育..........................................18
3.4 良性前列腺肥大的流行病學..............................20
3.5 良性前列腺肥大病因....................................20
3.6 前列腺的診斷..........................................21
第二章 研究材料與方法....................................23
第一節 研究架構..........................................23
第二節 藥品及儀器設備....................................24
2.1 藥品..................................................24
2.2 儀器設備..............................................24
第三節 尿液樣品及試劑配製................................27
3.1 尿液樣品來源..........................................27
3.2 基質溶液配製..........................................27
第四節 樣品前處理 .......................................28
4.1 尿液樣品的淨化 .......................................28
4.2 蛋白質濃度測定 .......................................28
4.3 三氯醋酸(Trichloracetic acid; TCA)沉澱..............28
4.4 蛋白質的消化(Protein Digestion).....................29
4.5 穩定同位素二甲基標定(Stable-Isotope Dimethyl Labeling)................................................29
第五節 蛋白質的分離......................................30
5.1 填充式十八烷卡匣分餾(Packing C18 cartridge fractionation)...........................................30
5.2 高效能液相層析分餾(HPLC fractionation)..............30
5.3 MALDI-TOF MS對經消化的尿液樣品之偵測..................31
5.4 液相層析儀(LC-MS)樣品製備...........................31
第六節 酵素免疫反應(ENZYME-LINKED IMMUNOASSAY; ELISA)..32
第七節 蛋白質資料庫鑑定..................................33
第三章 結果與討論........................................34
第一節 蛋白質基質輔助雷射脫附游離飛行時間質譜儀的分析結果........................................................34
1.1 ClinProTools軟體的分析................................34
1.2 接受者操作特徵曲線(Receiver Operating Characteristic Curve; ROC)分析..........................................37
第二節 液相層析/電灑游離-四極棒-飛行時間質譜儀的分析結果.38
2.1 液相層析分離..........................................38
2.2 穩定同位素標定(Stable Isotope Labeling).............39
2.3 LC-MS/MS質譜儀的分析結果..............................40
第三節 差異性蛋白質討論..................................43
3.1酵素免疫(ELISA)結果分析..............................43
第四章 結論..............................................49
參考文獻..................................................50
附錄......................................................58
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