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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 阮雪芬(Hsueh-Fen Fen) | |
| dc.contributor.author | Wei-Hsuan Wang | en |
| dc.contributor.author | 王薇瑄 | zh_TW |
| dc.date.accessioned | 2022-11-25T05:33:21Z | - |
| dc.date.available | 2026-09-20 | |
| dc.date.copyright | 2021-10-23 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-09-28 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/81970 | - |
| dc.description.abstract | 蛋白體學方法提供了現代科學更全面性研究的渠道，讓我們能更深入了解生物系統中複雜的交互作用，蛋白體學有別於傳統探討個別蛋白質，蛋白體學探討的是高通量的蛋白質混和物。蛋白質可以透過後轉譯修飾來調控蛋白質功能的活性，其中蛋白質磷酸化就是最常見的後轉譯修飾。我們利用整合磷酸化蛋白質體和蛋白質體學方法，探討了週期性拉伸誘導肺細胞的分子機制和粒線體分裂抑制劑於神經母細胞瘤的作用機制。在週期性拉伸實驗中，我們選擇人類肺細胞，因為人體的肺臟會因呼吸時收縮，所以細胞並不是處於靜止狀態，我們探討了肺癌細胞和肺纖維細胞間磷酸化蛋白質的程度，發現有對拉伸敏感的磷酸位點，也有細胞屬性特有的磷酸化反應位點。有趣的是，兩個細胞株在經過二十四小時的週期性拉伸後，粒線體傾向於分裂為體積更小的粒線體，除此之外，經過二十四小時拉伸的細胞，細胞排列的方向會垂直於拉伸方向。 粒線體被譽為細胞的能量工廠，尤其重要在需要大量傳輸訊息的神經細胞，其本體、觸手狀的軸突與樹突都可以發現粒線體的蹤影，粒線體對神經細胞是相當重要的。近幾年隨著顯微鏡學的進步，發現粒線體動態變化(Mitochondrial Dynamic)會影響細胞生理，而過去的研究指出粒線體的融合(Mitochondrial fusion)與分裂(Mitochondrial fission)支持了神經細胞不同階段的生長所需。粒線體分裂抑制劑(mdivi-1)是最常被拿來做粒線體融合分裂實驗的藥劑，但近年的研究發現，它影響的不只是粒線體的型態，在動物模型中被證明有助於減緩阿茲海默症，並影響了細胞週期。在本篇研究中，我們利用蛋白體學、磷酸蛋白體學和生物資訊學進行大數據分析，我們發現Mdivi-1 處理後的神經母細胞瘤細胞SK-N-BE(2)C 胞內絲胺酸(Serine)濃度上升，同時它也活化細胞凋亡路徑和降低神經醯胺(Ceramide)濃度，Mdivi-1 還會促進PSMA3S250 去磷酸化，有趣的是，我們發現Mdivi-1 會同時促進生存和死亡訊號，絲氨酸含量充足和粒線體融合屬於細胞存活訊號，而PSMA3S250 去磷酸化、細胞凋亡路徑和降低神經醯胺(Ceramide)濃度屬於細胞死亡訊號，我們推測因為死亡訊號大於存活訊號，所以經過24 小時處理後的神經母細胞瘤傾向死亡。我們希望透過此研究來挖掘目前未知的分子機制，也期望此項研究能神經母細胞瘤病患提供一個新的且有效的治療策略。 本篇論文使用了多維蛋白體學和標靶代謝體研究細胞週期性拉伸和粒線體分裂抑制劑對於癌細胞的作用機轉，希望未來能應用在肺癌與神經母細胞瘤的治療策略。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-25T05:33:21Z (GMT). No. of bitstreams: 1 U0001-2209202102322900.pdf: 14073522 bytes, checksum: 61c9973a021eed6ddc743bc662754352 (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | "Table of Contents 口試委員審定書 I 致謝 II 中文摘要 IV Abstract VI List of Figures XIII List of Tables XVI Abbreviation XVII Chapter 1 Introduction 1 1.1 Proteomics 1 1.2 Proteomic methodologies 3 1.3 Objective of thesis 4 Chapter 2 Quantitative Phosphoproteomics Reveals Cell Alignment and Mitochondrial Length Change under Cyclic Stretching in Lung Cells 6 2.1 Background 6 2.1.1 Cyclic stretch 6 2.1.2 Phosphoproteomics 7 2.1.3 Phosphorylation in response to cyclic stretch 8 2.2 Aim of this study 9 2.3 Material and methods 9 2.3.1 Cell cultures 9 2.3.2 Selection of cyclic stretch conditions 10 2.3.3 Cellular orientation measurement 10 2.3.4 Protein extraction 10 2.3.5 Phosphoproteome experiments 11 2.3.6 NanoLC-MS/MS Analysis 11 2.3.7 Phosphoproteomics data processing and analysis 12 2.3.8 Functional enrichment analysis of differential phosphoproteins 13 2.3.9 Transcriptomics data analysis 13 2.3.10. Immunofluorescence staining 13 2.3.11 Mitochondrial image analysis 14 2.3.12. Statistical analysis 15 2.4 Results 15 2.4.1 Cell surface area (CSA) determination 15 2.4.2 Quantitative Phosphoproteome of Lung Cells in Response to Cyclic Stretch 16 2.4.3 Functional enrichment of stretching-regulated phosphoproteins 17 2.4.4 Functional enrichment of stretching-regulated gene expression 18 2.4.5 Uniaxial cyclic stretch resulted in cell rearrangement 19 2.4.6 Cyclic stretch enhanced mitochondrial length 19 2.4.7 Global view of the phosphorylation events induced by cyclic stretch 20 2.5 Discussion 21 Chapter 3 Integrative proteomics, phosphoproteomics, and targeted metabolomics reveal the molecular mechanism of neuroblastoma cell death induced by mitochondrial division inhibitor 1 (mdivi-1) 24 3.1 Background 24 3.1.1 Neuroblastoma 24 3.1.2 Mitochondria dynamics 24 3.1.3 Proteomics and phosphoproteomics 25 3.2 Aim of this study 26 3.3 Materials and methods 27 3.3.1 Cell cultures 27 3.3.2 Drug treatment 27 3.3.3 Immunocytochemistry (ICC) 28 3.3.4 Image analysis 28 3.3.5 Plasmid construction and DNA manipulation 28 3.3.6 Experimental design and statistical analysis 29 3.3.7 Protein extraction 30 3.3.8 Phosphoproteome experiments 30 3.3.9 Proteome experiment 31 3.3.10 NanoLC-MS/MS Analysis 32 3.3.11 Mass spectrometric data analysis of the proteome and phosphoproteome 33 3.3.12 Functional enrichment 34 3.3.13 Kinase prediction 34 3.3.14 Western blot 35 3.3.15 L-serine quantification 36 3.3.16 Ceramide isolation 36 3.3.17 Instrumentation and data analysis for targeted metabolism analysis 37 3.3.18 Cell cycle analysis 37 3.3.19 Cell proliferation assay 38 3.3.20 Assessment of cell apoptosis 38 3.3.21 Statistical analysis 38 3.4 Results 39 3.4.1 Mdivi-1 blocks mitochondrial fission 39 3.4.2 Quantitative proteome of mdivi-1-treated SK-N-BE(2)C 39 3.4.3 Quantitative phosphoproteome analysis of mdivi-1-treated SK-N-BE(2)C 40 3.4.4 Functional enrichment of mdivi-1-mediated proteins and protein phosphorylation 41 3.4.5 Validation of proteomics and phosphoproteomics 42 3.4.6 Mdivi-1 influences serine levels and induces apoptosis through the regulation of ceramide 43 3.4.7 Continuously phosphorylated PSMA3-S250 facilitates cell proliferation 46 3.5 Discussion 47 Chapter 4 Future perspectives 51 Chapter 5 References 54 Figures 65 Tables 112 " | |
| dc.language.iso | en | |
| dc.subject | 細胞週期性拉伸 | zh_TW |
| dc.subject | 肺細胞 | zh_TW |
| dc.subject | 多體學 | zh_TW |
| dc.subject | 粒線體 | zh_TW |
| dc.subject | 粒線體抑制劑 | zh_TW |
| dc.subject | 絲氨酸 | zh_TW |
| dc.subject | 神經醯胺 | zh_TW |
| dc.subject | 神經母細胞瘤 | zh_TW |
| dc.subject | proteomics | en |
| dc.subject | lung cancer | en |
| dc.subject | neuroblastoma | en |
| dc.subject | ceramide | en |
| dc.subject | serine | en |
| dc.subject | mitochondrial division inhibitor 1 | en |
| dc.subject | mitochondria | en |
| dc.subject | cyclic stretch | en |
| dc.subject | phosphoproteomics | en |
| dc.title | 肺細胞週期性拉伸與神經母細胞瘤粒線體分裂抑制之蛋白體學研究 | zh_TW |
| dc.title | Proteomics of cyclic stretch in lung cells and mitochondrial division inhibition on neuroblastoma | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.advisor-orcid | 阮雪芬(0000-0003-4876-3309) | |
| dc.contributor.coadvisor | 黃宣誠(Hsuan-Cheng Huang) | |
| dc.contributor.coadvisor-orcid | 黃宣誠(0000-0002-3386-0934) | |
| dc.contributor.oralexamcommittee | 徐駿森(Hsin-Tsai Liu),許家郎(Chih-Yang Tseng),張心儀,黃翠琴,蔡懷寬 | |
| dc.subject.keyword | 多體學,肺細胞,細胞週期性拉伸,粒線體,粒線體抑制劑,神經母細胞瘤,絲氨酸,神經醯胺, | zh_TW |
| dc.subject.keyword | proteomics,phosphoproteomics,cyclic stretch,mitochondria,mitochondrial division inhibitor 1,serine,ceramide,neuroblastoma,lung cancer, | en |
| dc.relation.page | 184 | |
| dc.identifier.doi | 10.6342/NTU202103278 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2021-09-28 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 基因體與系統生物學學位學程 | zh_TW |
| dc.date.embargo-lift | 2026-09-20 | - |
| 顯示於系所單位： | 基因體與系統生物學學位學程 | |
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