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研究生:范誌桓
研究生(外文):Fan, Chih-Huang
論文名稱:以質譜法分析人類(一)乙醯化血紅蛋白; (二)唾 液蛋白之硝化與亞硝化的轉譯後修飾; (三)從採血 紙上萃取的血紅蛋白中硝化及氧化的穩定度
論文名稱(外文):Mass spectrometric analysis of (1) acetylated human hemoglobin, (2) nitrated and nitrosylated human salivary proteins, and (3) stability of nitration and oxidation in hemoglobin extracted from dried blood spot
指導教授:陳皓君
口試委員:王少君陳玉如
口試日期:2014-07-08
學位類別:碩士
校院名稱:國立中正大學
系所名稱:化學暨生物化學研究所
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:121
中文關鍵詞:質譜乙醯化硝化唾液蛋白採血紙人類血紅蛋白
外文關鍵詞:Mass spectrometryacetylationnitrationsalivary proteindried blood spothuman hemoglobin
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  • 被引用被引用:2
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蛋白質乙醯化與否和許多癌症有極大的相關性,在多數的癌症腫瘤中,組蛋白去乙醯酶 (HDAC)會有過量的表現。HDAC6被發現與肺癌有相關性,而在紅血球中也被發現含有 HDAC6,我們使用液相層析串聯式質譜儀對 10個非吸菸者和 10個吸菸者的血液萃取出的血紅蛋白進行分析,並對乙醯化修飾做相對定量,結果顯示,非吸菸者和吸菸者乙醯化程度並無差異性。
蛋白質的硝化被認為與發炎、神經退化性疾病及癌症具有相關性,我們用免疫親和性管柱搭配串聯式質譜分析了 15個唾液樣品,分別為 5個非吸煙者、5個吸煙者和52個口腔癌患者,在硝化蛋白中,到目前為止,鑑定到3次以上的硝化蛋白質有 15個,在亞硝化蛋白中,鑑定到 3次以上蛋白質則有 17個。
Dried blood spot (DBS)是一種新穎的微量分析技術,由於空氣中含有眾多的含氮氧反應性物種可能會導致蛋白質硝化及氧化,因此,我們用串聯式質譜儀對 從DBS上萃取出的血紅蛋白中硝化及氧化修飾做定量並評估其穩定度,發現在 14天內三種存放條件 (室溫、4 °C和 -20 °C)下的所有修飾的含量皆相似並無明顯變化。


Overexpression of histone deacetylase (HDACs) was observed in many cancer types. In red blood cells, HDAC6 was found and was related to lung cancer. The purpose of this study is to identify sites of acetylation in human hemoglobin and measure the extent of acetylation in each site by using nanoflow liquid chromatography−nanospray ionization tandem mass spectrometry (nanoLC-NSI/MS/MS). Among the 22 lysine residues in human hemoglobin, we found that acetylation took place at 7 sites. Semiquantification showed that the extents of modification at these sites for smokers and nonsmokers. According to the result, it has no difference in the extents of acetylation between smoker and nonsmoker.
Nitration of proteins is related to inflammation, neurological disease and cancer. We analyzed 15 salivary samples from smokers, nonsmokers and oral cancer patients by immunoaffinity column coupled with nanoLC-NSI/MS/MS. So far, we identified 134 nitroproteins and 105 nitrosoproteins in these samples.
Dried blood spot (DBS) is an emerging microsampling technology for bioanalysis. It remains unknown whether nitration and oxidation in hemoglobin can form artifactually during storage of DBS in air. Therefore, we analyzed hemoglobin extracted from DBS cards and evaluate the stability of its modifications. After placing the DBS cards at 4°C and at room temperature, we isolated hemoglobin from these cards and compared the extent of nitration and oxidation with direct extract hemoglobin. The extents of eleven modifications, including nitration and nitrosylation of tyrosine as well as oxidation of cysteine and methionine residues, in human hemoglobin were measured in the trypsin digest by nanoLC-NSI/MS/MS under the selected reaction monitoring (SRM) mode. The extents of all PTMs are stable up to 14 days at all conditions.

目錄
第一部份 1
利用奈升流速液相層析奈電噴灑串聯式質譜儀分析乙醯化血紅蛋白 1
1-1. 轉譯後修飾 (Post-translational modification, PTM) 4
1-2. 蛋白質乙醯化 4
1-3. 乙醯化修飾與癌症的關係 6
1-4. 本研究的目的與方法 6
2-1. 儀器 8
2-2. 藥品 8
2-3. 實驗方法 9
2-3-1. 市售人類血紅蛋白與乙酸酐反應 9
2-3-2. 利用有機溶劑萃取血紅蛋白 9
2-3-3. 螢光儀定量萃取的血紅蛋白 10
2-3-4. 血液樣品中的人類血紅蛋白之水解 10
2-3-5. 奈升流速液相層析質譜儀的分析 10
2-3-6. 序列資料庫的比對和數據分析 11
2-3-7.二維線性離子阱式傅立葉轉換電場軌道多次質譜儀(LTQ-Orbitrap XL) 12
2-3-8. 統計學分析 12
2-3-9. 血液樣品資料 13
3-1. 奈升流速液相層奈電噴灑法質譜儀分析經過胰蛋白酶水解過的人類血紅蛋白之乙醯化轉譯後修飾 14
3-2. 二維線性離子阱式傅立葉轉換電場軌道多次質譜儀 (LTQ-Orbitrap)分析經過胰蛋白酶水解過的乙醯化人類血紅蛋白之轉譯後修飾 17
3-3. 以不同濃度的乙酸酐與人類血紅蛋白反應,相對定量其酪胺酸乙醯的轉譯後修飾量 18
3-4. 分析血液中人類樣品中的血紅蛋白 23
第二部份 26
以免疫親和性管柱搭配液相層析串聯式質譜法分析唾液蛋白之硝化與亞硝化的轉譯後修飾 26
4-1. 蛋白質的硝化與疾病的相關性 29
4-2. 含 3-NT蛋白質的形成機制 30
4-3. 利用抗體分析含 3-NT蛋白質的分析方法 36
4-4. 本研究分析方法的建立 39
5-1. 儀器 41
5-2. 藥品與材料 41
5-3. 液相層析與固相萃取管柱 42
5-4. 實驗步驟 42
5-4-1. 樣品資料及來源 42
5-4-2. 唾液前處理 43
5-4-3. 唾液蛋白定量方法 43
5-4-4. 硝基酪胺抗體之免疫沈澱管柱製備 43
5-4-4-1. 抗體與Protein A/G之鍵結 44
5-4-4-2. 抗體與Protein A/G之交聯反應 44
5-4-4-3. 含3-NT胜肽之免疫沉澱 44
5-4-4-4. 含3-NT胜肽的沖提 45
5-4-5. 唾液蛋白的除鹽與濃縮步驟 45
5-4-5-1. 利用 Nanosep® 離心裝置對唾液蛋白的除鹽與濃縮 45
5-4-5-2. 利用一維膠體電泳唾液蛋白的除鹽與濃縮 46
5-4-5-3. 銀染 46
5-4-6. 唾液蛋白的水解 47
5-4-6-1. 經 Nanosep® 離心裝置除鹽後唾液蛋白的水解 47
5-4-6-2. 經一為膠體電泳除鹽後的唾液蛋白水解 48
5-7. 奈升液相層析奈噴灑游離串聯質譜儀分析條件 49
5-7-1. 液相層析系統條件 49
5-7-2. 質譜儀全質譜掃瞄模式條件 49
5-7-3. 質譜儀資料掃瞄模式條件 49
6-1. 唾液樣品的前處理 51
6-2. 唾液蛋白的定量 51
6-3. 利用抗 3-硝基酪胺抗體之免疫沈澱管柱純化唾液中的硝化蛋白 51
6-4. 分析免疫沉澱過程中未鍵結之蛋白質 52
6-5. 液相層析儀系統的最佳化 54
6-5-1. 比較使用 UPLC (1.7 μm)和 HPLC (5 μm)管柱的差異 56
6-6. 比較五次 IP實驗於 nanoLC-NSI/MS/MS的分析 57
6-7. 比較五次 IP實驗於一維膠體電泳除鹽濃縮後的分析方式 61
6-8. 統整與分類硝化與亞硝化蛋白質 66
第三部份 74
用奈升流速液相層析奈電噴灑串聯質譜儀分析從採血紙上萃取的血紅蛋白中硝化及氧化的穩定度 74
8-1. Dried blood spot的優點 77
8-2. 本研究的目的 77
8-3. 本研究的方法 78
9-1. 儀器 79
9-2. 藥品 80
9-3. 實驗步驟 80
9-3-1. 從採血紙上萃取血紅蛋白 80
9-3-2. 利用有機溶劑萃取血紅蛋白 81
9-3-3. 螢光儀定量萃取的血紅蛋白 81
9-3-4. 血液樣品中的人類血紅蛋白之水解 81
10-1. 從採血紙上萃血的萃取效率 82
10-2. 使用方法一比較血紅蛋白硝化和氧化修飾的程度 83
10-3. 使用方法二比較血紅蛋白硝化和氧化修飾的程度 86
第十一章 參考文獻 89
第十二章 附圖 97
第十三章 中英對照表 105
第十四章 縮寫表 108

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