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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 邱繼輝(Kay-Hooi Khoo) | |
| dc.contributor.author | Hsin-Hung Huang | en |
| dc.contributor.author | 黃興鴻 | zh_TW |
| dc.date.accessioned | 2021-06-17T04:25:47Z | - |
| dc.date.available | 2021-08-20 | |
| dc.date.copyright | 2018-08-20 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-08-14 | |
| dc.identifier.citation | Ashline, D., Singh, S., Hanneman, A., Reinhold, V. (2005) Congruent strategies for carbohydrate sequencing. 1. Mining structural details by MSn. Anal Chem. 77(19), 6250-62.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70319 | - |
| dc.description.abstract | 醣質體於癌症與疾病中的研究目標包含希望能找到醣化作用在病理生理機制中的變化。特別是醣鏈上的醣表位分析，除了是重要的基本醣生物學研究目標，更可能是非常重要的疾病標記。而目前以質譜技術進行各種免疫細胞類型中特定醣鏈上硫酸化、唾液酸化醣表位分析以及全面性的針對生物樣本中醣表位具體量化分析，仍然是非常艱鉅的挑戰，並且很少被報導。本論文以實驗室既有的醣質體分析平台方法為基礎，進行兩種不同方向的分析方法開發。首先以多孔石墨碳(porous graphitized carbon)管柱分離技術為基礎，開發奈米流速多孔石墨碳層析質譜方法平台，針對表現於N型醣鏈上的硫酸化醣抗原之唾液酸鍵接位點進行結構確認及相對比例定量。然而要精確定位醣鏈上硫酸化醣表位中硫酸根位置，則仍必須針對全甲基化醣鏈 (permethylated glycans) 進行二次與三次質譜實驗來確認。論文中結合不同分析方法的優點，能針對B-CLL患者收集的外周血單核細胞(PBMC) 上的抑制性B細胞受體 CD22上的特定硫酸化與唾液酸化醣鏈進行半定量監測。
而在另一方面，本論文的第二部分也是主要部分致力於探索不同的數據採集方法，來進行更全面醣質體研究的可行性。在此部分，本論文首次開發將數據獨立採集方法 (intelligent GlycOmics Data-independent-acquisition, iGODIA, method) 應用於醣表位全面性與相對量化分析。並以BSM ( Bovine Maxillary Mucin)樣品中的全甲基化非硫酸化與硫酸化 O型醣鏈完整測試此方法應用於不同分析模式，包含正負電分析，二次與三次質譜分析 (MS2, MS3)，以及應用此方法進行醣質體定性定量實驗 (Quan/Qual experiments)，並建立最佳數據獨立採集方法和其儀器參數。更進一步結合產物離子資訊依賴三次質譜方法 (MS3) ，進行同分異構醣表位的相對含量定量分析，與當前的LC-MS2-pd-MS3數據依賴性採集模式相比，應用此數據獨立性採集模式方法 (iGODIA) 針對結腸癌三期患者組織樣品的中的O型醣鏈上的特定醣表位進行定性定量分析，可證明此數據獨立性採集模式方法具備獨特分析優勢。 | zh_TW |
| dc.description.abstract | Cancer and disease glycomics aim to delineate the pathophysiological glycosylation changes of significant translational values. Ability to efficiently map the altered glycosylation features particularly the terminal glyco-epitopes (glycotopes) not only is essential to drive basic glycobiology research but also can uncover valuable disease markers. Despite well-recognized biological importance, high precision and comprehensive mass spectrometry (MS)-based glycomic identification and quantitative mapping of terminal glycotopes particularly the sulfo-, sialylated glycotopes on various immune cell types remains technically challenging and rarely reported. In this thesis work, MS-based (sulfo)-glycomic platform previously developed in the laboratory was extended by developing and incorporating additional complementary analytical approaches in two different aspects. First, nanoLC-MS/MS analysis of native N-glycans on capillary poros graphitized carbon column was investigated and shown to be a more efficient and direct way to resolve the sialyl linkages of N-glycans carrying sulfo-sialylated glycotopes. This allows semi-quantitative mapping of the relative expression of specific sulfo-sialylated ligands of an inhibitory B cell receptor, CD22, on the peripheral blood mononuclear cells (PBMC) collected from B-CLL patients. However, de novo sequencing and identification of the sulfated glycotopes down to the level of defining the position of sulfate was found to be more readily accomplished by MS2/MS3 analysis of permethylated glycans at higher sensitivity. To home in on this latter aspect, the second and major part of this thesis work was devoted to explore the feasibility of more comprehensive mapping via alternative data acquisition method. An intelligent GlycOmics DIA (iGODIA) workflow, including dual positive/negative polarity analysis, tandem MS2/MS3, and Qual/Quan experiments, were investigated using permethylated non-sulfated and sulfated O-glycan from BSM as respective standards in positive and negative ion modes to establish optimum data independent acquisition (DIA) setup and instrument parameters. Further product dependent (pd)-MS3 were applied following DIA to resolve isomeric targeted glycotopes and various modes of relative quantification were experimented. In comparison against current LC-MS2-pd-MS3 data dependent acquisition mode, the advantages and extra benefits of this iGODIA workflow were clearly demonstrated when target-adapted against glycotopes on O-glycans of colon cancer stage III patients' tissue samples. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T04:25:47Z (GMT). No. of bitstreams: 1 ntu-107-D95b46010-1.pdf: 4574045 bytes, checksum: 642a61e2ae8aabf9fdacb5e84d12ba92 (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | Table of Contents
Chapter 1 : Introduction 1 1.1 : Glycosylation and Glycomics 1 1.2 : Mass Spectrometry-Based Methods for Glycomics Study 7 1.2.1 : From FAB-MS to MALDI- and LC-ESI-MS 8 1.2.2 : Tandem MS and Glycan Sequencing 10 1.2.2.1 : MALDI MS/MS 11 1.2.2.2 : LC-ESI-MS/MS 13 1.2.2.3 : Orbitrap Mass Spectrometers for Multimode MS2/MS3 15 1.3 : The Limitation of Glycomics by Current Mass Spectrometry-Based Methods 18 1.4 : Specific Aims 23 Chapter 2 Materials and Methods 25 2.1 : Release of N- and O-glycans from Cell Line or Tissue 25 2.2 : N- and O-glycan Permethylation 26 2.3 : MALDI-MS and MS/MS Experiments 27 2.4 : PGC- and RP- NanoLC-MS with DDA experiment 28 2.5 : iGODIA & iGODIA tMS3 experiment 29 Chapter 3 Results 31 3.1 : To Establish a Complementary PGC-Based Method for Identifying Native 2,3- and/or 2,6-Sialyl Sulfated N-Glycan from Biological Source 32 3.1.1 : Results from MS and MS/MS Analysis of Permethylated N-glycans 33 3.1.2 : NanoPGC-LC/MS for Resolving Native Sulfo-Sialyl N-glycans 38 3.1.3 : Relative Quantification of KN343 Glycotope in B-CLL Samples by NanoPGC-LCMS Platform 42 3.2 : High Throughput MS-Based Method for Targeted Glycotope Quantitation 45 3.2.1 : Workflows of DDA and iGODIA Experiments 47 3.2.2 : iGODIA in Glycomics Study 53 3.2.2.1 : Determining the MS Scan Range and Stepped MS/MS Isolation Window in iGODIA Experiment 53 3.2.2.2 : The Comparison Between DDA and iGODIA 58 3.2.2.3 : Negative Ion Mode iGODIA Applied to Permethylated Mono-Sulfated O-Glycan Analysis .... 68 3.2.2.4 : Relative Quantitation of Targeted Glycotopes by iGODIA.... 71 3.2.2.5 : Relative Quantification of Isomeric Glycotopes by iGODIA with Targeted MS3.. 75 3.2.2.6 : Targeted Glycotopes Analysis of Permethylated O-Glycans of Colon Cancer Tissue by iGODIA... 81 Chapter 4 Discussion 89 4.1 : Strategies for Analytical Workflow 90 4.2 : Future Perspective for LC/MS Based Method Development 95 References 97 | |
| dc.language.iso | en | |
| dc.subject | 同分異構醣表位 | zh_TW |
| dc.subject | 醣表位 | zh_TW |
| dc.subject | 醣質體 | zh_TW |
| dc.subject | 數據獨立採集方法 | zh_TW |
| dc.subject | iGODIA | en |
| dc.subject | glycomics | en |
| dc.subject | isomeric glycotopes | en |
| dc.subject | glycotopes | en |
| dc.subject | DIA | en |
| dc.title | 全面性醣表位精準鑑定分析之質譜方法建立與應用 | zh_TW |
| dc.title | Development of Mass Spectrometry-Based Methods for Comprehensive and Quantitative Mapping
of Terminal Glycotopes | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 廖寶琦(Pao-Chi Liao),張權發(Chuan-Fa Chang),蕭鶴軒(He-Hsuan Hsiao),辜韋智(Wei-Chi Ku) | |
| dc.subject.keyword | 醣表位,醣質體,同分異構醣表位,數據獨立採集方法, | zh_TW |
| dc.subject.keyword | glycomics,glycotopes,DIA,iGODIA,isomeric glycotopes, | en |
| dc.relation.page | 105 | |
| dc.identifier.doi | 10.6342/NTU201803292 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-08-15 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
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