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研究生:陳薇如
研究生(外文):Wei-Ju Chen
論文名稱:1. 表面輔助雷射脫附游離質譜法應用於急性肝臟型紫質症之快速檢測 2. 利用微波輔助降低胰蛋白酶水解胜肽定序過程中導致之天門冬醯酸去醯胺化程度
論文名稱(外文):1. Rapid Screening Assay of Acute Hepatic Porphyria in Urine with Surface-Assisted Laser Desorption/Ionization Mass Spectrometry. 2. A Microwave-Assisted Procedure to Reduce Asn Deamidation Artifacts during trypsin peptide mapping. 2. A Microwave-Assisted Procedure to Reduce Asn Deamidation Artifacts during trypsin peptide mapping.
指導教授:賴建成賴建成引用關係
口試委員:卓群恭陳朝榮
口試日期:2016-07-27
學位類別:碩士
校院名稱:國立中興大學
系所名稱:分子生物學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:125
中文關鍵詞:急性肝臟型紫質症快速檢測微波輔助水解去醯胺化質譜儀
外文關鍵詞:Acute Hepatic Porphyriarapid screening assaymicrowave-assisted digestiondeamidationmass spectrometry
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[論文題目一]
紫質症 (porphyria) 是一群因血基質合成路徑中的合成酵素發生病變所導致的罕見代謝疾病總稱,其中急性肝臟型紫質症為最嚴重的類型。在醫院,大多以尿液檢測之代謝物為判斷疾病的主要依據,其初步檢測為當患者尿液中的 aminolevulinic acid (ALA) 及 porphobilinogen (PBG) 的含量顯著上升時,表示已處於急性發作的情況。近年來,由於質譜儀具有較高靈敏度及專一性等優點,已成為診斷臨床之紫質症的重要工具之一,其中表面輔助雷射脫附游離法 (surface-assisted laser desorption/ionization, SALDI) 於先前的文獻已得知其具高通量、高靈敏度及可對小分子做定量等特性。因此,本篇研究的目的為利用 SALDI-TOF MS 建立一個快速篩選且可一次分析多個樣品的檢測急性肝臟型紫質症平台。而本實驗以奈米碳材之無機奈米粒子作為主要輔助 ALA 及 PBG 之基質並對其進行條件最佳化,且預期找尋適合之濃縮輔助的其他無基基質,藉此建立一個快速篩檢且高通量檢測急性肝臟型紫質症之平台,於結果可發現 C60 相較於傳統有機基質 (CHCA 和 DHB)、其他碳材基質 (graphene nanoplatelets grade 5, graphene nanohorns, single-layer graphene oxide, 2-4 few-layer graphene oxide, 4-8 multi-layer graphene oxide),其性能較優異。於最佳化條件的測試中,可發現 C60 溶於 ddH2O 且濃度為 10 ppm時,以薄層法 (thin-layer method) 進行樣品製備且以 SALDI-TOF MS 之負電模式進行 PBG 的偵測時,其效果最佳。且以此條件進行 ALA 及 PBG 之偵測極限測試時,可測得 ALA 為 2.5 ppm,PBG 為 1 ppm,已低於正常人之濃度。綜合以上,本篇已建立一種快速、靈敏及高通量的平台,可對尿液中的 ALA 及 PBG 進行定性分析,未來期望應用於急性肝臟型紫質症患者之臨床檢測。

[論文題目二]
Asparagine 脫胺作用為生物體當中常見的蛋白質轉譯後修飾,會從 asparagine (Asn) 轉變成 aspartate (Asp),此作用常發生於蛋白質藥物表現時常會出現的作用,如果發生此作用時可能會導致因為改變蛋白質的結構,進而影響蛋白質的活性,其中此作用於人體內常會導致免疫反應。由於 asparagine 脫胺作用有以上負面影響,因此有效的減少消化治療性蛋白質上的 asparagine 脫胺修飾進行準確的定量備受高度期望。傳統上,蛋白質定量通常是利用抗原抗體結合方法進行分析,但在過去的十幾年,由於質譜發展迅速,液相層析儀-串聯式質譜儀 (LC-MS/MS) 已成為替代分析的工具之一。目前已知在傳統的蛋白質樣品前處理之蛋白酶 (Trypsin) 消化作用時,有 80 % 會產生脫胺作用。至今,大多文獻皆調整條件進行降低脫胺作用,如消化作用中的緩衝液類型及濃度、環境的 pH 值及溫度等,尚未利用微波輔助之方式,因此本篇實驗目的在於利用微波輔助降低 asparagine 脫胺作用。首先,以低解析度質譜儀測試 PENNY 胜肽經由及不經過傳統還原及烷化反應後,於 37 度 C 反應 16 小時、高功率微波 (900 W) 1 分鐘及低功率微波 (100 W) 30 分鐘,結果顯示,只有直接進行高功率微波的 PENNY 胜肽沒有 asparagine 脫胺作用。接著利用高解析度質譜儀測試 16 小時、4 小時、高功率微波 1 分鐘及低功率微波 30 分鐘分別直接進行反應及經由傳統還原及烷化反應後進行分析,結果顯示,直接進行高功率及低功率微波的 PENNY 胜肽皆不會導致 asparagine 脫胺作用。接著測試單獨的還原反應、單獨的烷化反應和還原及烷化反應於傳統方法 (37 度 C,30 分鐘) 及微波輔助 (900 W,5 分鐘),結果顯示傳統進行還原及烷化反應時,會產生脫胺作用,因此證明微波皆不會導致 asparagine 脫胺作用。最後測試高功率及低功率微波輔助平台,於結果驗證,不論是高功率微波或是低功率微波輔助之平台,在 PENNY 胜肽中都可完全降低 asparagine 脫胺作用。未來希望除了可應用於藥品的品管上,亦可應用於其他蛋白質之 Asn 脫胺作用之相關研究。

[論文題目一]
The porphyrias are a group of rare inherited metabolic disorders of heme biosynthesis and acute hepatic porphyria is the most serious type of porphyria. In hospital, the concentrations of aminolevulinic acid (ALA) and porphobilinogen (PBG) in random urine are used for the diagnosis of acute porphyria, owing to the concentration of ALA and PBG will get higher in patient urine. Recently, mass spectrometry has better performance on sensitivity and specificity, it offered an alternative tool for porphyria clinical studies. Surface-assisted laser desorption/ionization time-of-flight mass spectrometry (SALDI-TOF MS) are known for its high throughput, high sensitivity and the ability of the quantification of small molecules. In this study, our purpose is to establish a rapid and high-throughput platform for the screen of acute hepatic porphyria patients by using SALDI-TOF MS. In results, fullerene C60 has the best performance compared with other traditional organic matrix (CHCA and DHB) and carbon materials (graphene nanoplatelets grade 5, graphene nanohorns, single-layer graphene oxide, 2-4 few-layer graphene oxide, 4-8 multi-layer graphene oxide). Then, the parameters of C60 are optimized by using PBG, including the solution (ddH2O), concentration (10 ppm), SALDI-TOF MS mode (negative mode) and sample preparation (thin-layer method). And the limits of detection were 2.5 ppm for ALA and 1 ppm for PBG. Overall, we establish a simple, sensitive and high-throughput technique for the detection of ALA and PBG in urine, it can help us to screen the acute porphyria patients.

[論文題目二]
Deamidation is a common protein post-translational modification, it can convert asparagine (Asn) into aspartate (Asp), and it’s also a common degradation mechanism of protein pharmaceuticals. The changes in protein structure occurs when deamination modifies in the active part of protein residue. Since deamidation has negative impacts on protein pharmaceuticals, accurate quantitation of Asn deamidation in protein pharmaceuticals is highly demanded. Traditional method of protein quantification is based on antigen-antibody binding assay. Owing to the fast development of mass spectrometry, liquid chromatography-tandem mass spectrometry (LC-MS/MS) has become an alternative analytical platform in decades. So far, up to 80% of protein samples have the modification of deamidation in traditional trypsin digestion. Nowadays, many studies investigate appropriate parameters for decreasing deamination, such as the contains, concentrations, pH, temperature of buffer in digestion, etc. However, there’s no study investigate the effect of microwave-assisted digestion. In this study, the purpose is to establish a non asparagine deamidation of trypsin digestion by using microwave-assisted method. First, PENNY peptides were reduced and alkylated in traditional method and direct incubated in 37℃ for 16 hr, or in microwave-assisted method, 900 W (high power) for 1 min,100 W (low power) for 30 min, and they were analyzed by using low-resolution MS (LTQ-XL), it showed that only direct incubated in high power has no Asn deamidation. Next, PENNY peptides were incubated in 37℃ for 16 hr, 4 hr, microwave 900 W for 1 min,100 W for 30 min directly or in traditional method, and they were analyzed by using high-resolution MS (TripleTOF 6600), it indicated that direct incubation in high and low power has no Asn deamidation. Then, only reduction, only alkylation, reduction-alkylation in traditional method (37℃ for 30 min) or microwave-assisted method (900 W for 5 min) were analyzed. It showed that reduction-alkylation in traditional method resulted in the modification of deamidation. Therefore, it confirmed that microwave-assisted method can decrease asparagine deamidation. Finally, the platform of trypsin digestion in high or low power microwave-assisted method were tested, the results showed that both high and low power microwave-assisted method had no Asn deamidation in PENNY peptide. In future, this platform can be applied on the quality control of protein pharmaceuticals, and help the researches about Asn deamination.

[論文題目一]
第一章 緒論
第一節 前言 I-1
第二節 紫質症之介紹 I-2
2.1 紫質症的病因及分類 I-2
2.2 急性肝臟型紫質症 I-3
2.3 急性肝臟型紫質症於臨床診斷方法及質譜上的研究 I-3
第三節 質譜儀之介紹 I-5
第四節 基質輔助雷射脫附游離法之介紹 I-6
4.1 MALDI 的基本原理 I-6
4.2 MALDI 的特性 I-7
4.3 MALDI 的優缺點 I-8
第五節 表面輔助雷射脫附游離法之介紹 I-10
5.1 SALDI 的基本原理 I-10
5.2 SALDI 的特性 I-10
第六節 無機奈米基質 I-11
6.1 石墨烯 I-11
6.2 氧化鐵奈米粒子 I-13
6.3 二氧化鈦奈米粒子 I-14
第七節 研究動機 I-15
第八節 實驗流程 I-16
第二章 研究材料與設備
第一節 藥品與溶劑 I-17
第二節 實驗儀器 I-18
第三章 材料與方法
第一節 尋找適合的基質作為輔助 SALDI 之材料 I-19
1.1 標準品溶液配製 I-19
1.2 LC-ESI MS/MS 標準品確認 I-19
1.3 有機基質的溶液配製 I-19
1.4 奈米碳材無機基質的不同溶劑配製與質譜模式最佳化測試 I-19
1.5 最佳基質的不同濃度最佳化測試 I-20
1.6 最佳基質的不同點盤最佳化測試 I-20
1.7 外部校正基質配製 I-20
第二節 預濃縮測試 I-21
2.1 無機基質溶液配製 I-21
2.2 預濃縮的測試 I-21
第三節 平台的確認 I-22
3.1 標準品偵測極限測試 I-22
3.2 真實樣品-正常人尿液的測試 I-22
第四節 質譜儀器裝置 I-22
第四章 結果與討論
第一節 各基質對 PBG 標準品進行脫附游離輔助時所扮演的角色 I-24
第二節 選出最佳基質及輔助 PBG 標準品脫附游離的最佳化條件 I-27
第三節 選出有效縮短樣品前處理時間的適合基質 I-31
第四節 利用最佳化條件進行PBG及ALA標準品的偵測極限測試 I-36
第五節 利用最佳化的條件進行真實樣品_正常人尿液測試 I-36
第五章 結論 I-43
附錄-圖表
附表一、MALDI 常用的基質與適用分析物 I-43
附圖一、血基質合成途徑 I-44
附圖二、紫質症的臨床症狀 I-44
附圖三、質譜儀的基本結構 I-45
附圖四、MALDI / SALDI-TOF MS 的結構圖 I-45
附圖五、MALDI 的原理 I-46
附圖六、MALDI 的樣品製備方式 I-46
附圖七、以石墨稀為基礎延伸發展之材料 I-47
參考文獻 I-48

[論文題目二]
第一章 緒論
第一節 前言 II-1
第二節 脫胺作用之介紹 II-2
2.1 脫胺作用對於人體的影響 II-2
2.2 Asparagine脫胺作用對於藥物品管的影響 II-3
2.3 Asparagine 脫胺作用之蛋白質體於質譜上的研究 II-3
第三節 微波輔助酵素水解之介紹 II-6
第四節 質譜儀之介紹 II-7
4.1 樣品導入系統 II-7
4.2 離子源 II-8
4.3 質量分析器 II-9
第五節 研究動機 II-9
第六節 實驗流程 II-10
第二章 研究材料與設備
第一節 藥品與溶劑 II-11
第二節 實驗儀器 II-11
第三章 材料與方法
第一節 找尋可完全降低 asparagine 脫胺作用的處理方法 II-12
1.1 標準品的溶液配製 II-12
1.2 以 LC-ESI MS/MS 做標準品的確認 II-12
1.3 篩選合適 PENNY 胜肽的條件 II-12
1.4 測試還原及烷化作用是否會導致 asparagine 脫胺作用 II-12
1.5 測試微波輔助平台是否會導致 asparagine 脫胺作用 II-13
第二節 確認微波輔助平台可完全降低 asparagine 脫胺作用 II-13
2.1 標準品的溶液配製 II-13
2.2 胰蛋白之消化作用 II-13
第三節 質譜儀器裝置 II-14
3.1 初步分析 II-14
3.2 主要分析 II-14
第四節 蛋白質資料庫比對 II-15
第四章 結果與討論
第一節 以較低解析度之質譜儀 (LTQ-XL) 進行初步測試 II-16
1.1 確認樣品 (PENNY 胜肽) II-16
1.2 測試微波是否有 asparagine 脫胺作用 II-16
1.3 測試 DTT 和 IAM 是否有 asparagine 脫胺作用 II-22
第二節 以較高解析度之質譜儀 (Q-TOF) 進行平台建立 II-22
2.1 測試微波是否有 asparagine 脫胺作用 II-22
2.2 測試 DTT 和 IAM 是否有 asparagine 脫胺作用 II-32
2.3 測試微波平台是否有 asparagine 脫胺作用 II-42
第三節 比較高功率微波及低功率微波平台 II-42
第五章 結論 II-46
附錄-圖表
附圖一、Asn脫胺作用過程 (Cheng L. et.al., 2007) II-47
附圖二、ESI 原理 II-47
參考文獻 II-48

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