請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/92308完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 徐丞志 | zh_TW |
| dc.contributor.advisor | Cheng-Chih Hsu | en |
| dc.contributor.author | 鄭凱文 | zh_TW |
| dc.contributor.author | Kai-Wen Cheng | en |
| dc.date.accessioned | 2024-03-21T16:32:51Z | - |
| dc.date.available | 2024-03-22 | - |
| dc.date.copyright | 2024-03-21 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-02-02 | - |
| dc.identifier.citation | Chapter 1.Introductory Chapter
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/92308 | - |
| dc.description.abstract | 代謝組學是指探討生物樣本中的代謝物（如體液、細胞和組織）以發現生物標記物。其中，質譜法其具有高靈敏度、選擇性和高掃描速度等特性，得以在化學層級上作為分析代謝物中一種合適的方法。然而，基於質譜法的代謝組學正在面臨一些挑戰，如樣品某些代謝物的含量較低或同時存在著不同極性和離子化性質的代謝物以及較低含量的代謝物導致鑑定上有困難。為了解決這些挑戰，本論文提出了使用奈米級微流液相層析結合多噴嘴發射器來增強儀器靈敏度，以及使用化學衍生化的方法來提高代謝物的離子化效率以及分離效果。這些方法可以提高低含量代謝物的檢測以及優化代謝組學的分析流程。
第一部份，本論文呈現出單細胞分析的多模式平台，此平台使用奈米級微流液相層析和多噴嘴發射器質譜儀以及單細胞選擇技術結合，以研究群體和亞群體內的代謝組學異質性。我們透過此分析平台，分別從單顆人類骨肉瘤細胞和膠質母細胞瘤細胞中鑑定出15和17種脂類。單細胞選擇技術還被用來分離具有DNA損傷反應和快速遷移的異常亞族群細胞並且透過分析平台進一步探討代謝組學差異。此多模式平台提供了一種有前途的單細胞代謝組學微量尺度之分析方法，為細胞異質性提供了有價值的洞察。 第二部份，本論文呈現出使用高性能化學同位素標記平台對非酒精性脂肪性肝病進行全面的代謝組學分析。其中非酒精性脂肪性肝病進一步分類為非酒精性脂肪肝和非酒精性脂肪性肝炎。我們的研究包括代謝組和總體基因體學數據的相關性分析。該研究鑑定出潛在的生物標記物，可以使用非侵入性之程序在血漿中準確地診斷非酒精性脂肪性肝病之亞型與健康對照組。同時，該研究還探討了非酒精性脂肪性肝病亞型患者的肝臟和尿液樣本，進一步透過代謝通路分析發現其相關代謝物可能會被調控以緩解非酒精性脂肪性肝病進展。此外，總體基因體學分析確定了在非酒精性脂肪肝中具有上下調控的特定細菌物種，暗示了腸道菌群失調和其疾病發展之間的聯繫。這些資訊可能有助於進一步研究非酒精性脂肪肝病的疾病機制和治療方法的發展。 | zh_TW |
| dc.description.abstract | Metabolomics refers to the study of metabolites in biological samples such as biofluids, cells, and tissues to discover biomarkers. Mass spectrometry (MS) is a powerful tool for analyzing metabolites at a chemical level due to its high sensitivity, selectivity, and fast scanning speed. However, MS-based metabolomics faces challenges including lower sample abundance, coexistence of metabolites with diverse polarities and ionization properties, and difficulty identifying low-abundance compounds.
To address these challenges, the dissertation proposes using nanoflow liquid chromatography combined with multinozzle emitters to enhance the sensitivity of instrument, chemical derivatization to improve metabolite ionization and separation efficiency. These methods can improve the detection of low-abundance metabolites and overall quality of metabolomics results. First of all, the dissertation presents the multimodal platform for single-cell analysis that combines nanoflow liquid chromatography and multinozzle emitters MS with a functional single-cell selection (fSCS) pipeline to investigate metabolomics heterogeneity within the population and subpopulation. Using this platform, 15 and 17 lipids were identified from single human osteosarcoma and glioblastoma cells, respectively. The fSCS pipeline was also used to isolate and we analyzed the aberrant subpopulations of cells with DNA damage response and fast migration. This multimodal platform offers a promising approach for the nano-to-micro analysis of single-cell metabolomics, providing valuable insights into cell heterogeneity. Second, the dissertation presents the comprehensive metabolomic profile of non-alcoholic fatty liver disease (NAFLD) by analyzing four different specimens using high-performance chemical isotope labeling (CIL) platform. Our investigation includes correlation analyses between metagenomic and metabolomic data. We have identified potential biomarkers that can accurately diagnose the presence of nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), and healthy control status in plasma using a non-invasive procedure. Moreover, the results of the metabolomics pathway analysis may suggest that metabolites were regulated to alleviate the progression of NAFLD by inhibiting ROS and reducing lipid accumulation in the liver, as demonstrated by different specimens. Additionally, metagenomic analyses pinpoint specific bacterial species with up- or down-regulation in NAFLD, suggesting a link between gut microbiota dysbiosis and NAFLD development. Overall, these chapters offer significant insights into metabolomics'' potential applications and advancements. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-03-21T16:32:51Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-03-21T16:32:51Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 謝誌 i
中文摘要 iv Abstract v Table of Contents vii List of Figures x List of Tables xiv Chapter 1. Introductory Chapter 1 1-1 Reaserch roadmap 1 1-2 References 7 Chapter 2. Investigating the Metabolic Heterogeneity of Cancer Cells Using Functional Single-Cell Selection and nLC Combined with Multinozzle Emitter Mass Spectrometry…. 11 2-1 Abstract 11 2-2 Introduction 12 2-3 Results and discussion 15 2-3-1 An evaluation of the emitter performance between the single nozzle and the multinozzle was performed 15 2-3-2 Cell populations were differentiated using the nLC-single-cell mass spectrometer analysis platform 17 2-3-3 The metabolomic profiles of U2OS cells under DDR-induced by ionizing radiation… 23 2-3-4 Investigated the metabolomic profiles of GBM cells by analyzing the migration patterns of fast and slow cells 26 2-4 Conclusion 30 2-5 Acknowledgments 31 2-6 Materials and methods 31 2-6-1 Chemicals and reagents 31 2-6-2 Cell culture 31 2-6-3 Functional single-cell selection pipeline 32 2-6-4 Cells lipid extraction 33 2-6-5 Nanoflow liquid chromatography (nLC) Single-cell MS analysis platform… 33 2-6-6 Data analysis and metabolites identification 35 2-7 Supplementary information 36 2-8 Reference 42 Chapter 3. Investigate Metabolic Pathways and Potential Biomarkers of Non-Alcoholic Fatty Liver Disease via Metabolomics and Metagenomics 48 3-1 Abstract 48 3-2 Introduction 49 3-3 Results 53 3-3-1 Characterization of the study cohort 53 3-3-2 Metabolomics profiling for NAFLD compared to healthy controls was conducted on plasma and fecal specimens 56 3-3-3 Metabolomics pathway analysis was performed on plasma and fecal specimens between NAFLD and healthy control groups 59 3-3-4 Metabolomics profiling was performed on plasma and fecal specimens to identify potential biomarkers for distinguishing between NAFL, NASH, and healthy control groups 63 3-3-5 The metabolomics profiling comparing NASH to NAFL was performed using urine and liver specimens 72 3-3-6 Comparison of the gut microbiome taxonomy profiles of healthy control and NAFLD group 77 3-3-7 The Strategy of correlation analysis between metagenomics and metabolomics 83 3-3-8 Correlation analysis of metagenomics and metabolomics in fecal and plasma specimens. 85 3-4 Discussion 99 3-5 Conclusion 106 3-6 Material and method 108 3-6-1 Chemicals and reagents 108 3-6-2 Sample preparation 108 3-6-3 Dansylation labeling 109 3-6-4 LC-MS analysis 110 3-6-5 Data processing and metabolites identification 115 3-6-6 Sample collection, preparation and data processing of metagenomics 116 3-7 Supplementary information 118 3-8 References 119 Appendix 130 Chapter 4. Perspective 153 4-1 Ready for primetime of Single-cell metabolomics by mass spectrometry? 153 4-2 Advancements in understanding and NAFLD through biomarkers investigation and gut bacteria dysbiosis hypothesis 155 4-3 References 159 | - |
| dc.language.iso | en | - |
| dc.subject | 化學衍生化 | zh_TW |
| dc.subject | 單細胞分析 | zh_TW |
| dc.subject | 脂質體學 | zh_TW |
| dc.subject | 代謝體學 | zh_TW |
| dc.subject | 非酒精性脂肪性肝病 | zh_TW |
| dc.subject | 質譜法 | zh_TW |
| dc.subject | chemical derivatization | en |
| dc.subject | mass spectrometry | en |
| dc.subject | single-cell analysis | en |
| dc.subject | lipidomics | en |
| dc.subject | metabolomics | en |
| dc.subject | non-alcoholic fatty liver disease | en |
| dc.title | 基於質譜法之代謝組學整合性策略:從單細胞分析到疾病標誌物之研究 | zh_TW |
| dc.title | Integrated Strategies in Mass Spectrometry-Based Metabolomics: From Single-Cell Analysis to Disease Biomarker Investigation | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-1 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 何佳安;陳冠元;廖曉偉;許邦弘;陳盈嵐 | zh_TW |
| dc.contributor.oralexamcommittee | Ja-an Annie Ho;Guan-Yuan Chen;Hsiao-Wei Liao;Pang-Hung Hsu;Ying-Lan Chen | en |
| dc.subject.keyword | 質譜法,單細胞分析,脂質體學,代謝體學,非酒精性脂肪性肝病,化學衍生化, | zh_TW |
| dc.subject.keyword | mass spectrometry,single-cell analysis,lipidomics,metabolomics,non-alcoholic fatty liver disease,,chemical derivatization, | en |
| dc.relation.page | 160 | - |
| dc.identifier.doi | 10.6342/NTU202400517 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2024-02-06 | - |
| dc.contributor.author-college | 理學院 | - |
| dc.contributor.author-dept | 化學系 | - |
| dc.date.embargo-lift | 2029-02-02 | - |
| 顯示於系所單位： | 化學系 | |
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