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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/68062完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 牟中原(Chung-Yuan Mou) | |
| dc.contributor.author | Jen-Hsuan Chang | en |
| dc.contributor.author | 張仁瑄 | zh_TW |
| dc.date.accessioned | 2021-06-17T02:12:00Z | - |
| dc.date.available | 2023-01-27 | |
| dc.date.copyright | 2018-01-27 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-01-03 | |
| dc.identifier.citation | 2.5 Reference
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Takeda, Efficient chromosomal transposition of a Tc1/mariner-like transposon Sleeping Beauty in mice, P. Natl. Acad. Sci. USA, 2001, 98, 9191-9196. 18. K. Horie, K. Yusa, K. Yae, J. Odajima, S. E. J. Fischer, V. W. Keng, T. Hayakawa, S. Mizuno, G. Kondoh, T. Ijiri, Y. Matsuda, R. H. A. Plasterk and J. Takeda, Characterization of Sleeping Beauty transposition and its application to genetic screening in mice, Mol. Cell. Biol., 2003, 23, 9189-9207. 19. K. J. Clark, A. M. Geurts, J. B. Bell and P. B. Hackett, Transposon vectors for gene-trap insertional mutagenesis in vertebrates, Genesis., 2004, 39, 225-233. 20. E. C. Olivares, R. P. Hollis, T. W. Chalberg, L. Meuse, M. A. Kay and M. P. Calos, Site-specific genomic integration produces therapeutic Factor IX levels in mice, Nat. Biotechnol., 2002, 20, 1124-1128. 21. K. Kawakami and A. Shima, Identification of the Tol2 transposase of the medaka fish Oryzias latipes that catalyzes excision of a nonautonomous Tol2 element in zebrafish Danio rerio, Gene, 1999, 240, 239-244. 22. A. Koga, A. Iida, M. Kamiya, R. Hayashi, H. Hori, Y. Ishikawa and A. Tachibana, The medaka fish Tol2 transposable element can undergo excision in human and mouse cells, J. Hum. Genet., 2003, 48, 231-235. 23. C. Miskey, Z. Izsvak, R. H. Plasterk and Z. Ivics, The Frog Prince: a reconstructed transposon from Rana pipiens with high transpositional activity in vertebrate cells, Nucleic Acids Res., 2003, 31, 6873-6881. 24. E. T. Prak and H. H. Kazazian, Jr., Mobile elements and the human genome, Nat. Rev. Genet., 2000, 1, 134-144. 25. A. H. Farley, E. T. Luning Prak and H. H. Kazazian, Jr., More active human L1 retrotransposons produce longer insertions, Nucleic Acids Res., 2004, 32, 502-510. 26. W. Chen, P.-H. Tsai, Y. Hung, S.-H. Chiou and C.-Y. Mou, Nonviral cell labeling and differentiation agent for induced pluripotent stem cells based on mesoporous silica nanoparticles, Acs Nano, 2013, 7, 8423-8440. 27. J. H. Chang, P. H. Tsai, W. Chen, S. H. Chiou and C. Y. Mou, Dual delivery of siRNA and plasmid DNA using mesoporous silica nanoparticles to differentiate induced pluripotent stem cells into dopaminergic neurons, J. Mater. Chem. B, 2017, 5, 3012-3023. 28. https://www.ncbi.nlm.nih.gov/genbank/. 29. F. P. Chang, Y. Hung, J. H. Chang, C. H. Lin and C. Y. Mou, Enzyme encapsulated hollow silica nanospheres for intracellular biocatalysis, Acs. Appl. Mater. Inter., 2014, 6, 6883-6890. 30. F. P. Chang, Y. P. Chen and C. Y. Mou, Intracellular implantation of enzymes in hollow silica nanospheres for protein therapy: cascade system of superoxide dismutase and catalase, Small, 2014, 10, 4785-4795. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/68062 | - |
| dc.description.abstract | 基因轉染，指的是將外源基因插入特定細胞，藉由基因重組的方式讓細胞能夠朝著特定方向發展，或是能夠應用至基因治療。神經再生是被廣泛討論的議題，緣由是神經細胞一但受損，其自癒能力差，容易造成永久性傷害，如阿茲海默症、帕金森氏症等。因此，近幾年來研究學者於再生醫學的領域不斷在探討神經分化的相關研究，並且引入基因治療。提及基因治療，過去較廣泛使用病毒載體來進行基因轉染，進而讓細胞能表達特定基因，也進一步研究此特定基因後續影響的機制。也有不少研究，透過轉染基因至幹細胞中，促進幹細胞分化成特定功能性細胞。然而，病毒載體轉染基因雖已商業化，但仍有潛在風險，例如：基因隨機插入細胞染色體而造成基因突變、細胞癌化等，因此後來研究學者致力於開發非病毒載體，希望能將非病毒載體提升轉染基因的效率，進一步廣泛應用於臨床實驗。本論文中共分三個主題，第一、二部分則是與神經分化相關的研究。然而短暫 (transient) 表現的質粒 (plasmid) 攜帶基因進入細胞中，其效果有限，甚至必須做連續轉染 (serial transfection) 來增強基因轉殖效率。因此在本論文中第三部分我們引入轉位子 (transposon) 質粒，透過中孔洞奈米矽材將基因送入細胞，達到永久表現、甚至將細胞做成新的細胞克隆 (cell clones)。我們將此技術應用在肺癌細胞，希望能夠讓門冬酰胺酶 (asparaginase) 基因於癌細胞中表現、進一步能夠造成癌細胞凋亡，作為飢餓治療。
以下是本論文的三個主題： (1) 透過中孔洞奈米矽材作為非病毒基因載體，轉染中樞神經重要基因 Nurr1 (Nuclear receptor related-1) 於誘導性多能性幹細胞 (induced pluripotent stem cells, 簡稱為 iPSCs)，促進 iPSCs分化為多巴胺功能性神經細胞 (dopaminergic neurons) (2) 透過中孔洞奈米矽材作為非病毒基因載體，同時轉染三種不同關鍵基因 Ascl1 (Achaete-scute homolog 1), Brn2 (POU domain transcription factor) 及 Myt1l (Myelin Transcription Factor 1 Like)，以及攜帶一促進神經分化小分子 (Isoxazole 9, ISX-9) 將老鼠體細胞直接分化為多巴胺神經細胞 (3) 結合睡美人轉位子 (Sleeping Beauty transposon) 及中孔洞奈米矽材作為非病毒基因載體，應用於肺癌細胞的飢餓治療 以上三個主題分別於本論文中的第三、四及第五章。本論文第一章中分成兩部分：第一部分介紹病毒及非病毒載體作為基因療法的作用機制及相關背景，第二部分則概述中孔洞奈米矽材的歷史及合成方法。論文中第二章則分享實驗方法，包含中孔洞奈米矽材的合成鑑定、細胞實驗以及後續分析方法。最後一章則總結所有工作，以及分享本論文的成果對於未來能夠持續發展的研究。 | zh_TW |
| dc.description.abstract | Gene delivery is a method of introducing the foreign genomic materials into the specific cells to carry out the gene therapy. Neural regeneration is an essential issue, because the neurons are difficult to repair after injury. The nonviral-based vehicles were needed for gene delivery, to avoid the integration effect of the chromosome, gene mutagenesis and immune issues associated with the viral vehicles. In my first research topic, mesoporous silica nanoparticles (MSNs) were used in the DNA delivery and co-delivery with siRNA for differentiation of dopaminergic neurons from induced pluripotent stem cells (iPSCs). In the second research topic, the MSNs were utilized to deliver three different genes and a small molecule for direct conversion of dopaminergic neurons from mouse fibroblasts. The results showed that MSNs as an efficient, minimally cytotoxicity and effective non-viral carriers for gene delivery, and MSNs had great potential in cell-oriented therapeutic applications. In the third research topic, we first combine the Sleeping Beauty transposon plasmid and MSNs for the delivery of asparaginase (ASN) gene into the cancer cells to prolong the ASN gene expression in the lung cancer cells. In addition, the stable cell clones could be successfully generated by the treatment of puromycin, and the ASN was expressed in the cells after doxycycline was added.
There are six chapters in this thesis: Chapter 1: to give an introduction of gene therapy and the background of non-viral based nanoparticles, including mesoporous silica nanoparticles Chapter 2: the experimental section of nanoparticles synthesis, in vitro studies of plasmid release and cell-associated experiments Chapter 3: dual delivery of siRNA and plasmid DNA using mesoporous silica nanoparticles to differentiate induced pluripotent stem cells into dopaminergic neurons Chapter 4: generation of functional dopaminergic neurons from reprogramming fibroblasts by nonviral-based mesoporous silica nanoparticles Chapter 5: Sleeping Beauty transposon-mediated asparaginase gene delivery by a nanoparticle platform Chapter 6: summary and the perspective of my studies. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T02:12:00Z (GMT). No. of bitstreams: 1 ntu-107-D02223109-1.pdf: 7016874 bytes, checksum: ba8dae6258a61794f78672c96bac4a1e (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 致謝 2
中文摘要 4 Abstract 6 List of contents: 8 List of Figures: 14 List of Tables: 24 Abbreviations 26 Chapter 1. General Introduction 29 1.1 Gene therapy and the strategies 29 1.1.1 Viral infection 30 1.1.2 Non-viral gene delivery 31 1.2 Backgrounds of mesoporous silica Nanoparticles (MSNs) 33 1.2.1 Synthesis of MSNs 33 1.2.2 Biological applications of MSNs 35 1.3 Reference 38 Chapter 2. Dual Delivery of siRNA and Plasmid DNA using Mesoporous Silica Nanoparticles to Differentiate Induced Pluripotent Stem Cells into Dopaminergic Neurons 46 2.1 Abstract 46 2.2 Introduction 47 2.2.1 Induced pluripotent stem cells, development of non-viral transfection 47 2.2.2 The motivation of using mesoporous silica nanoparticles (MSNs) as a nanocarrier of plasmid and siRNA and the backgrounds of MSNs 48 2.2.3 Nurr1 gene, Rex1 gene, and dopaminergic neuron-related gene 48 2.2.4 The purpose of the research 49 2.3 Results and Discussion 52 2.3.1 Characterization of FMSN(+) 52 2.3.2 Study of DNA-siRNA-FMSN(+) (pNurr1-siRex1-FMSN(+)) complex using Gel electrophoresis 54 2.3.3 Study of in vitro plasmid release profile 57 2.3.4 Cellular Uptake and endosome escape of FMSN(+) 59 2.3.5 Cytotoxicity of FMSN(+) on iPSCs 61 2.3.6 Determination of mRNA-expression levels for neuron genes by qRT-PCR 63 2.3.7 Dual delivery of pNurr1 and siRex1 synergistically enhances a number of dopaminergic neurons 66 2.3.8 Significant cell morphology conversion, as observed by a microscope 80 2.4 Conclusion 82 2.5 Reference 83 Chapter 3. Generation of Functional Dopaminergic Neurons from Reprogramming Fibroblasts by Nonviral-based Mesoporous Silica Nanoparticles 93 3.1 Abstract 93 3.2 Introduction 94 3.2.1 The background of direct conversion by trans-differentiation 94 3.2.2 Mesoporous silica nanoparticles (MSNs) as a nanocarrier of small molecular and plasmids for direct conversion of somatic cells 95 3.3 Results and discussion 97 3.3.1 Characterizations of mesoporous silica nanoparticles 97 3.3.2 Mesoporous silica nanoparticles uptaken by MFs 100 3.3.3 Mesoporous silica nanoparticles mediate nontoxic bio-nanomaterial for MFs 102 3.3.4 mRNA expression level of neural reprogramming factors by qRT-PCR 103 3.3.5 Significant cell morphology conversion 106 3.3.6 Serial nonviral delivery of neural reprogramming factors promotes Tuj1+ and Dat+ cells efficiently and the expression of the neural lineage markers 107 3.3.6 Enhanced expression of dopamine transporter and maturation of functional neurons 110 3.4 Conclusion 114 3.5 Reference 115 Chapter 4. Sleeping Beauty Transposon-Mediated Asparaginase Gene Delivery by a Nanoparticle Platform 119 4.1 Abstract 119 4.2 Introduction 120 4.2.1 The introduction of enzyme therapy 120 4.2.2 Sleeping Beauty transposon as a plasmid vector and the motivation of this study 121 4.3 Results and discussion 123 4.3.1 Characterizations of mesoporous silica nanoparticles modified with amine group 123 4.3.2 Mesoporous silica nanoparticles uptaken by human lung cancer cells, endosome escape of FMSN 125 4.3.3 Cytotoxicity of ASN, PEI-layered MSN, PEI and pSB-ASN transfected by PEI-layered MSN in human adenocarcinoma cells 130 4.3.4 Transfection efficiency analysis 133 4.3.4 Protein-level identification of asparaginase 134 4.3.5 Generation of ASN-expressed cell clones 135 4.4 Conclusion 138 4.5 Reference 139 Chapter 5. Experimental section 143 5.1 Experimental method of chapter 3 (Topic 1) 143 5.1.1 The generation of iPSCs and Culture 143 5.1.2 The synthesis of FITC Conjugated Mesoporous Silica Nanoparticles, FMSNs, FMSN(+) 143 5.1.3 pNurr1-siRex1-FMSN(+) Adsorption and Agarose Gel Electrophoresis 144 5.1.4 Labeling of RITC-pNurr1 and in vitro plasmid release analysis 145 5.1.5 Cellular Cytotoxicity 145 5.1.6 Cellular uptake analysis by flow cytometry analysis 146 5.1.7 iPSCs Transfection and in vitro Neuron Differentiation 146 5.1.8 Quantitative Reverse Transcriptase Polymerase Chain Reaction 147 5.1.9 Immunofluorescence Staining 149 5.1.10 Quantification of the Relative Protein Level of Dopaminergic neurons using Flow Cytometry analysis 150 5.1.11 Western blotting 151 5.1.12 Measurement of dopamine release 151 5.1.13 Statistical analysis 152 5.1.14 Thermogravimetric analysis 152 5.1.15 X-ray diffraction 152 5.2 Experimental methods of chapter 4 (Topic 2) 153 5.2.1 Synthesis of APTMS Conjugated Mesoporous Silica Nanoparticles, MSN-NH2 153 5.2.2 Modification of MSN-NH2-biotin-avidin (abbreviated as MSN-avi) 153 5.2.3 ISX-9/Rh800 loading 154 5.2.4 Small molecule (Rh800) release 154 5.2.5 pABM-I@M Adsorption and Agarose Gel Electrophoresis 154 5.2.6 Cellular Cytotoxicity/ Cell proliferation 155 5.2.7 Flow cytometry analysis 155 5.2.8 FM4-64 staining of endosome after pABM-I@M delivery 155 5.2.9 MFs Transfection and generation of MF-neuron cells 156 5.2.10 Quantitative Reverse Transcriptase Polymerase Chain Reaction 157 5.2.11 Immunofluorescence Staining of MF-neuron 158 5.2.12 Measurement of dopamine release by enzyme-linked immunosorbent assay 159 5.3 Experimental methods of chapter 5 (Topic 3) 161 5.3.1 Synthesis of amine-group conjugated mesoporous silica nanoparticles 161 5.3.2 Molecular cloning 161 5.3.3 Cellular Cytotoxicity of PEI-layered MSN 162 5.3.4 Cell culture and transfection 162 5.3.5 Cell selection 163 5.3.6 Cell uptake analysis 163 5.3.7 Western blot 164 Chapter 6. Conclusions and Perspective 165 | |
| dc.language.iso | zh-TW | |
| dc.title | 中孔洞奈米矽材於轉染基因上的應用 | zh_TW |
| dc.title | Non-Viral Gene Delivery by Mesoporous Silica Nanoparticles | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 陳逸聰(Yit-Tsong Chen),戴桓青(Hwan-Ching Tai),邱世華(Shih-Hwa Chiou),陳惠文(Huei-Wen Chen),凌嘉鴻(Steven Lin) | |
| dc.subject.keyword | 中孔洞奈米矽材,基因轉染,誘導型多功能幹細胞,多巴胺神經,睡美人轉位子,門冬?胺?,肺腺癌細胞, | zh_TW |
| dc.subject.keyword | mesoporous silica nanoparticles,gene delivery,induced pluripotent stem cells,dopaminergic neurons,Sleeping beauty transposon,asparaginase,human adenocarcinoma cells, | en |
| dc.relation.page | 166 | |
| dc.identifier.doi | 10.6342/NTU201800011 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-01-04 | |
| dc.contributor.author-college | 理學院 | zh_TW |
| dc.contributor.author-dept | 化學研究所 | zh_TW |
| 顯示於系所單位： | 化學系 | |
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