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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/94962完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 黃祥博 | zh_TW |
| dc.contributor.advisor | Hsiang-Po Huang | en |
| dc.contributor.author | 陳姿宇 | zh_TW |
| dc.contributor.author | Tzu-Yu Chen | en |
| dc.date.accessioned | 2024-08-21T16:56:14Z | - |
| dc.date.available | 2024-08-22 | - |
| dc.date.copyright | 2024-08-21 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-07-29 | - |
| dc.identifier.citation | 1. D'Avanzo F, Rigon L, Zanetti A, Tomanin R. Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment. Int J Mol Sci. 2020;21(4).
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/94962 | - |
| dc.description.abstract | 第二型黏多醣症 (MPS II) 由於己醛糖酸鹽硫酸脂酶 (IDS) 缺乏，導致醣胺聚醣 (GAG)的積累。第二型黏多醣症嚴重型會引起漸進性神經性退化以及死亡，而目前的治療方法無效。因此，在本研究中，我們從四名患有第二型黏多醣症嚴重型的患者生成多株誘導性多能幹細胞 (iPSCs) 及其同基因對照組 (isogenic control, ISO)。這些第二型黏多醣症幹細胞 (MPS II-iPSCs) 能成功分化成第二型黏多醣症特異性皮質神經元，顯示出特徵性生化和細胞表型，包括磷酸化 tau 陽性軸突珠串和明顯的電生理異常。然而，這些缺陷在同基因對照組 (ISO) 分化的神經元中大部分都獲得改善，這表明MPS II-iPSC分化的神經元能忠實地呈現第二型黏多醣症皮質神經元的病理生理特徵。在分析RNA-seq數據後，我們發現MPS II成熟神經元與健康受試者相比，Wnt/β-catenin、p38 MAP激酶和鈣信號通路的基因表達存在差異。基於這些失調的通路，我們使用這種成熟的第二型黏多醣症神經元平台測試了幾種相關化合物和藥物。一種高度選擇性的小分子肝醣合成酶激酶3β (GSK3β) 抑製劑顯著改善第二型黏多醣症神經元神經元的存活率、神經突形態和電生理異常。如我們的研究所示，第二型黏多醣症誘導性多能幹細胞平台揭示了第二型黏多醣症中神經元退化和死亡的機制，並可能有助於評估治療候選藥物。此外，這項工作表明第二型黏多醣症相關的神經元功能障礙在早期並非不可逆轉，針對第二型黏多醣症神經元中GAG積累所導致下游的失調信號通路進行治療，可能有助於挽救神經退化過程。 | zh_TW |
| dc.description.abstract | Mucopolysaccharidosis type II (MPS II), due to iduronate-2-sulfatase deficiency, leads to glycosaminoglycans (GAG) accumulation. Severe MPS II causes progressive neurodegeneration and death, while current treatments are ineffective. To this end, in the present study, we generated several clones of induced pluripotent stem cells (iPSCs) and their isogenic control (ISO) from four patients affected with the serve form of MPS II. The MPS II-iPSCs were successfully differentiated into MPS II-specific cortical neurons showing the characteristic biochemical and cellular phenotypes, including phosphorylated tau-positive axonal beading and distinct electrophysical abnormalities. However, these deficits were largely rescued in ISO-iPSC-neurons, indicating that the MPS II-iPSC-derived neurons faithfully displayed the pathophysiological features of MPS II cortical neurons. After analyzing RNA-seq data, we identified differences in the gene expression of the Wnt/β-catenin, p38 MAP kinase, and calcium signaling pathways in MPS II mature neurons compared to controls. Based on these dysregulated pathways, several related chemicals and drugs were tested using this mature MPS II neuron-based platform. A highly selective small molecule glycogen synthase kinase 3β (GSK3β) inhibitor significantly ameliorated neuronal survival, neurite morphology, and electrophysiological defects in MPS II neurons. Thus, the MPS II iPSC platform is valuable for dissecting the mechanism of neuronal degeneration and death in MPS II and may help evaluate therapeutic candidates. In addition, this study suggests that MPS II-associated neuronal dysfunction is not irreversible at the early stage and that targeting the dysregulated signaling pathways downstream of GAG accumulation in MPS II neurons may help to rescue the neurodegenerative process. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-08-21T16:56:14Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-08-21T16:56:14Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 論文口試委員審定書 I
謝辭 II 中文摘要 III Abstract IV I. PREFACE 1 Research Background 1 Motivation and Objectives 1 II. INTRODUCTION 1 Lysosome and Lysosomal Storage Diseases (LSDs) 1 Glycosaminoglycan 2 Mucopolysaccharides (MPS) 2 Clinical Manifestations of Mucopolysaccharidosis Type II (MPS II) 3 Neurological Involvement 3 Cardiopulmonary Complications 4 Skeletal Deformities 4 Orthopedic manifestations such as joint stiffness and skeletal deformities are prevalent among MPS II patients. Restricted joint range of motion and skeletal abnormalities, including dysostosis multiplex, are notable issues affecting the quality of life. 4 Visceral Involvement 5 Current Therapeutic Approaches and Their Limitations: Enzyme Replacement Therapy (ERT) cannot cross the Blood-Brain Barrier (BBB). 6 Current Strategies of MPS II Treatment 7 Ongoing Research and Future Directions 10 Introduction to Induced Pluripotent Stem Cells (iPSCs) 10 Brief History and Origin of iPSCs 10 The Properties and Identification of iPSCs 11 Advantages of Using iPSCs for MPS II 11 Key Research Studies on Using iPSCs for Modeling LSD, including MPS II 14 Potential Therapeutic Approaches Using iPSCs for MPS II 15 Signaling Pathways and Neurodegeneration 18 Wnt/β-Catenin Pathway in Neurodevelopment and Neurodegenerative Diseases 18 p38 MAP Kinase Pathway in Neurodevelopment and Neurodegenerative Diseases 21 Calcium Signaling Pathway in Neurodevelopment and Neurodegenerative Diseases 24 Impact of Wnt/β-Catenin Pathway, p38 MAP Kinase Inhibition, and Calcium Signaling on Lysosomal Storage Diseases 28 Advantages of Gene Editing and its Application in Stem Cells 31 Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) 32 Potential Involvement of These Signaling Pathways in MPS II Neurodegeneration 33 THE OBJECTIVE OF THIS STUDY 33 Rationale 33 SPECIFIC AIMS 34 III. RESEARCH DESIGN AND METHODS 34 Research Design 34 Material and Methods 35 Collection of human samples and subject recruitment 35 Generation of MPS II-iPSC 36 Healthy male control iPSCs and the culture of iPSCs 36 In vitro differentiation of MPS II-iPSCs 37 Teratoma formation assay 37 Karyotyping 38 Reverse transcription-polymerase chain reaction (RT-PCR) along with quantitative real-time reverse transcription PCR (qRT-PCR). 38 Alkaline phosphatase staining 39 IF staining 39 Generation of IDS mutation-corrected isogenic control (ISO) iPSCs 40 Neuronal differentiation of iPSCs 40 IDS activity determination 41 XTT assay 41 Cellular glycosaminoglycan content 42 Electrophysiology and neurite length detection 42 RNA sequencing and gene pathway analysis 44 Western blotting 45 Flow cytometry analysis and fluorescence-activated cell sorting (FACS) sorting 46 Luciferase reporter assay 47 Assays for cell viability 47 ChIP analysis 47 Intracellular Calcium measurements 48 Statistical analysis 49 Results 50 Generation of MPS II-iPSCs and their ISO-iPSC clones 50 MPS II-iPSCs manifested characteristic MPS II phenotypes 51 MPS II-iPSC-derived neurons exhibited lysosomal/autophagic abnormalities and axonal beadings 51 Neurite morphology, cytoskeletal protein expressions, and electrophysiology show anomalies in long-term cultured MPS II neurons. 52 Identification of dysregulated genes and pathways in MPS II neurons 54 Dysregulated calcium homeostasis in MPS II neurons and the possible mechanisms 56 Selected drug candidates rescued abnormalities in MPS II neurons. 57 Tideglusib reversed functional and morphological aberrations in MPS II neurons 58 Regulation of ion channel genes in iPSC-derived neurons by p38 MAPK and Wnt/β-catenin signaling 59 Discussion 59 Conclusion 66 Figure Legends 67 Figure 1. Generation of the MPS II-specific iPSCs. 67 Figure 2. Identification of IDS Mutations in MPS II-iPSCs through DNA Sequencing 68 Figure 3. Pluripotency Markers in MPS II-iPSCs 69 Figure 4. The capability of MPS II-iPSCs to differentiate into three germ layers. 70 Figure 5. Experimental Principle of A to G Base Editing and Generation and Characterization of the MPS II-Specific Isogenic Control iPSCs. 71 Figure 6. MPS II-iPSCs recapitulated the pathophysiological features of MPS II. 73 Figure 7. Neuron Differentiation and GFAP Expression Analysis in MPS II-iPSCs 74 Figure 8. MPS II-iPSCs derived cortical neurons recapitulated the pathophysiological features of MPS II. 76 Figure 9. Lysosomal marker expression in controls and MPS II-iPSC derived neurons. 78 Figure 10. Reduced Autophagy Flux in MPS II Neurons after Chloroquine Treatment 80 Figure 11. Assessment of Axonal Beading and Tau Pathology in MPS II Neurons Compared to Controls 82 Figure 12. Aberrant Neurite Morphology in MPS II Neurons. 84 Figure 13. Reduced Expression of NEFL in MPS II Neurons. 86 Figure 14. Reduced Expression of Ankyrin G and Spectrin in MPS II Neurons. 88 Figure 15. Abnormal Action Potentials in MPS II Neurons 90 Figure 16. The second set of Abnormal Action Potentials in MPS II Neurons 92 Figure 17. Comparison of Neuron Subtype Composition in 20-Week MPS II and HC Neurons 94 Figure 18. Neuronal phenotypes of MPS II-iPSC-derived excitatory (CaMKII α) and inhibitory (mDlx) neurons. 95 Figure 19. Impaired Action Potential Characteristics in 22-Week MPS II Excitatory Neurons 97 Figure 20. Transcriptome profiling revealed significant alterations in signaling pathways in MPS II neurons and distinct expression profiles of ion channel markers. 99 Figure 21. KEGG Pathway Analysis of Differentially Expressed Genes in MPS II vs. HC Neurons 101 Figure 22. GSEA and KEGG Pathway Analysis of Wnt Signaling in 15-Week MPS II Neurons 102 Figure 23. Altered Phosphorylation of GSK-3β and β-Catenin in 15-Week MPS II Neurons 104 Figure 24. Altered Subcellular Distribution of Active β-Catenin in 15-Week MPS II Neurons 106 Figure 25. Differential Expression of Wnt-Associated Genes in MPS II vs. Control Neurons 107 Figure 26. Reduced Wnt Signaling Activity in 15-Week MPS II Neurons 109 Figure 27. Reduced FGF Signaling and Altered p38 MAPK Distribution in 15-Week MPS II Neurons 110 Figure 28. Decreased Phosphorylation of p38 MAPK in 15-Week MPS II Neurons 112 Figure 29. Gene Activation Dynamics in 15-Week MPS II and HC Neurons after WNT3A and bFGF2 Treatment 114 Figure 30. Enriched Calcium Ion Regulation and Channel Gene Expression in MPS II Neurons 116 Figure 31. Altered Calcium Signaling Pathway in 15-Week MPS II Neurons Validated by RNA-seq and qRT-PCR 118 Figure 32. Elevated Baseline and Thapsigargin-Induced Calcium Levels in 15-Week MPS II Neurons 120 Figure 33. Effects of HS and GSK3β Inhibitors on Calcium Channel Gene Expression in 15-Week Neurons 122 Figure 34. Gene Expression Changes in Calcium Signaling Pathway after Ionomycin and Verapamil Treatment in 15-Week Neurons 124 Figure 35. Cytotoxicity Assessment of Various Drugs in 4-Week and 15-Week HC and MPS II Neurons 125 Figure 36. Therapeutic effects of selected drugs and chemicals on MPS II neurons 127 Figure 37. Drug Effects on Viability of MPS II Neurons 129 Figure 38. Differential Rescue Effects of Drugs on Gene Expression in 15-Week MPS II Neurons 131 Figure 39. Rescue of Axonal Beading (Tau-1) in 15-Week MPS II Neurons by Tideglusib Treatment 133 Figure 40. Rescue of Axonal Beading (p-tau) in 15-Week MPS II Neurons by Tideglusib Treatment 135 Figure 41. Tideglusib treatment reversed the calcium anomalies in MPS II neurons. 137 Figure 42. Cytotoxicity and Wnt Signaling Activation by Tideglusib in 4-Week and 15-Week HC and MPS II Neurons 139 Figure 43. Tideglusib treatment reversed the action potential anomalies in MPS II neurons. 141 Figure 44. Tideglusib Rescues Neurite Morphology in 15-Week MPS II Neurons 143 Figure 45. Modulation of Wnt/β-catenin, p38 signaling, and ion channel genes by different small molecules in control and MPS II neurons 145 Figure 46. β-Catenin Binding to LEF1/TCF Motif within SCN9A Promoter in 15-Week Neurons 147 Figure 47. Schematic depiction of a hypothetical model illustrating signaling pathway alterations and cellular phenotypes in MPS II neurons 149 Figure 48. Schematic illustration of a hypothetic model for cellular phenotypes in MPS II neurons. 151 Figure 49. Schematic Illustration of Hypothetical Model for Calcium-Related Cellular Phenotypes in MPS II Neurons 153 Table 1. Significant changes in p38 MAPK and PI3K signaling in MPS II Neurons identified by IPA of DEGs 155 Table 2. Concentration of cytotoxicity 50% (CC50) values of selected drugs in 4-week and 15-week HC and MPS II neurons 156 Reference 157 Appendix 183 與本論文相關之已公開發表之第一作者文獻 183 | - |
| dc.language.iso | zh_TW | - |
| dc.title | 利用病患特異性的誘導性多能幹細胞探討第二型黏多醣症的神經退化性病變機制及測試藥物 | zh_TW |
| dc.title | Mechanistic Study and Drug Testing for Neurodegeneration in Mucopolysaccharidosis Type II Using Patient-Specific Induced Pluripotent Stem Cells | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 黃憲松;李明學;林炫沛;張以承;謝松蒼 | zh_TW |
| dc.contributor.oralexamcommittee | Hsien-Sung Huang;Ming-Shyue Lee;Shuan-Pei Lin;Yi-Cheng Chang;Sung-Tsang Hsieh | en |
| dc.subject.keyword | 第二型黏多醣症II型,誘導性多能幹細胞,神經性退化性,皮質神經細胞,Wnt/β-catenin路徑,鈣信號傳導路徑,替格魯西布, | zh_TW |
| dc.subject.keyword | Mucopolysaccharidosis Type II (MPS II),Induced pluripotent stem cells (iPSCs),Neurodegeneration,Wnt/β-catenin signaling,Calcium signaling,Tideglusib, | en |
| dc.relation.page | 200 | - |
| dc.identifier.doi | 10.6342/NTU202402355 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2024-07-29 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 基因體暨蛋白體醫學研究所 | - |
| 顯示於系所單位： | 基因體暨蛋白體醫學研究所 | |
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