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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/79819完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳玉如(Yu-Ju Chen) | |
| dc.contributor.author | Hung-Ming Chien | en |
| dc.contributor.author | 簡鴻名 | zh_TW |
| dc.date.accessioned | 2022-11-23T09:12:34Z | - |
| dc.date.available | 2021-08-20 | |
| dc.date.available | 2022-11-23T09:12:34Z | - |
| dc.date.copyright | 2021-08-20 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-08-11 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/79819 | - |
| dc.description.abstract | 在腦中所發現之蛋白質包含體為漸凍人症候群中的主要病徵，其亦被懷疑與疾病的發展有關。而TDP-43蛋白質作為病患組織中蛋白質包含體的主要成分，其經常被發現具有過度磷酸化、過度泛素化之現象，同時此蛋白質亦可進一步遭受裁剪而成具類澱粉蛋白性質之片段。除了TDP-43蛋白質以外，近期的研究發現自第九號染色體之第七十二號開放閱讀框突變基因轉譯之甘胺酸-丙胺酸雙肽蛋白質(Glycine-alanine dipeptide repeats)亦沉積於病患之神經元中，且其亦具類澱粉蛋白質之特性。隨著越來越多的研究表明TDP-43蛋白質與甘胺酸-丙胺酸雙肽蛋白質於疾病中可能扮演著重要的角色，針對這些蛋白質的定性實驗亦顯得更加重要。然而，這些蛋白質的生物物理與生物化學性質之研究卻由於其溶解度與快速聚集等因素而備受阻礙。 為了克服這些困難以研究這些蛋白質之特性，我們設計並利用固相化學方法合成了一系列的胜肽探針，其由甘胺酸-丙胺酸雙肽蛋白質片段、八離胺酸肽片段(Octalysine)、與甲氧基硝基苯(Methoxynitrobenzene)衍生物作為橋接所組成。這些探針可有效的增進甘胺酸-丙胺酸雙肽蛋白質片段之溶解度、預防其片段自我聚集、並能夠於細胞中藉由紫外光照實行可控制之釋放。利用此探針並結合顯微鏡技術，我們發現甘胺酸-丙胺酸雙肽蛋白質片段會先行組裝成類澱粉蛋白質寡聚物(Amyloid oligomer)並進一步聚集成類澱粉蛋白質纖維；此胜肽探針亦可幫助釐清甘胺酸-丙胺酸雙肽蛋白質片段之詳細生物物理與生物化學特性。另外，藉由表達可於核質穿梭之螢光蛋白質於細胞系統內，我們發現到甘胺酸-丙胺酸雙肽蛋白質片段會導致細胞內之核質運輸功能異常。而利用電子顯微鏡觀察探針處理過後之細胞切片，我們亦注意到此片段會引起細胞核膜之內陷與不正常之折疊；另一方面，於進一步的免疫染色與生物化學實驗中，我們亦證實了甘胺酸-丙胺酸雙肽蛋白質片段類澱粉蛋白質寡聚物可引起脂質膜之穿透性增加。我們亦於後續的細胞實驗中發現甘胺酸-丙胺酸雙肽蛋白質片段可引起TDP-43蛋白質於細胞質內之不正常堆積，其現象與先前文獻所報導之病理特徵相似。 事實上，除了甘胺酸-丙胺酸雙肽蛋白質外，亦有研究證明了TDP-43蛋白質羧基端之裁剪片段亦可於細胞內引起TDP-43之蛋白質病理。因此，我們設計並合成了於還原環境中藉由雙硫鍵觸發之自釋放胜肽探針以研究TDP-43蛋白質羧基端之裁剪片段之堆疊。我們於此研究中仔細地觀測其胜肽探針裂解過程與釋放出之TDP-43片段之類澱粉蛋白質特性。 總結來說，我們成功利用甲氧基硝基苯或雙硫鍵之化學以設計並製備了一系列之胜肽探針。我們更進一步於其相對應之系統中，詳細觀測了TDP-43蛋白質裁剪片段與甘胺酸-丙胺酸雙肽蛋白質片段之生物物理與生物化學性質。我們期許在未來可藉由這些蛋白質片段之定性研究成果來幫助釐清漸凍人疾病發生之病因。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-23T09:12:34Z (GMT). No. of bitstreams: 1 U0001-0508202116155100.pdf: 25102259 bytes, checksum: 4d6a83301932353ce962fa6180812bd9 (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | "Acknowledgement ii 摘要 iii Abstract v Table of Contents vii List of Figures ix List of Tables x List of Abbreviations xi Chapter 1 : Photoinduced GA DPRs Oligomers Disrupted the Nuclear Membrane and Caused TDP-43 Cytosolic Retention 1 I. Introduction 1 1-1 Amyotrophic lateral sclerosis 1 1-2 C9orf72 gene mutation in ALS 3 1-3 The roles of GA DPRs in ALS pathology 13 1-4 Correlations between GA DPRs and TDP-43 14 1-5 Research aims and experimental design 15 II. Material and Methods 21 2-1 Material and instruments list 21 2-2 Probe preparation and identification 23 2-3 General sample preparation for in vitro measurements 25 2-4 Circular dichroism spectroscopy 25 2-5 Dye-binding assay 26 2-6 Turbidity measurements 26 2-7 Dot-blot assay 26 2-8 Infrared Spectroscopy 27 2-9 Transmission electron microscopy 27 2-10 Dynamic light scattering 28 2-11 Fluorescence-lifetime imaging microscopy 28 2-12 Direct stochastic optical reconstruction microscopy 30 2-13 Cell maintenance, Transfection, and Probe treatment 31 2-14 Cell lysate staining 32 2-15 Immunohistochemistry and Confocal microscopy 33 2-16 Total internal reflection fluorescence microscopy 33 2-17 Ex vivo antibody accessibility assay 34 2-18 Calcein-leakage assay 34 2-19 Seeding assay 35 2-20 Primary cortical neurons culture, Probe treatment and Neurite Fragmentation Analysis 36 2-21 Imaging quantification and Statistical analysis 37 III. Results 41 3-1 Preparation of photoinducible GA DPRs probes 41 3-2 Biophysical biochemical characterization of GA DPRs 43 3-3 GA DPRs formed amyloid oligomers and turned into fibrils. 46 3-4 GA DPRs caused nucleocytoplasmic transport defects 50 3-5 GA DPRs compromised nuclear membrane 59 3-6 GA DPRs induced endogenous TDP-43 mislocalized to cytoplasm 67 3-7 Introduction of GA DPRs promote degeneration in mouse cortical neurons 70 IV. Discussion 73 4-1 ADP-1 as a feasible tools for C9orf72 pathology studies 73 4-2 GA DPRs amyloid oligomers and their toxicities. 74 4-3 Comparison between GA and PR DPRs in nuclear transport defect 75 4-4 Conclusion and prospect 76 V. Reference 78 Chapter 2 : Developing the Auto-releasing Peptide Probe for Protein Fragment Aggregation Studies 86 I. Introduction 86 1-1 Amyloidogenic sequence of TDP-43 in ALS 86 1-2 Delivery of peptides and proteins into cytoplasm 87 1-3 Research aim and experimental design 88 II. Material and Methods 90 2-1 Material and instruments list 90 2-2 Synthesis and characterization of auto-releasing probe 91 2-3 General sample preparation for in vitro measurements 93 2-4 UV-Vis spectroscopy 93 2-5 Transmission electron microscopy 93 III. Results 94 3-1 Preparation of probe JJS-4 JJS-5 94 3-2 In vitro characterization of auto-releasing probes 97 IV. Discussion 99 4-1 Comparison between photoinducible probe and auto-releasing probe 99 4.2 Conclusion and prospect 100 V. Reference 101 " | |
| dc.language.iso | en | |
| dc.subject | 漸凍人症 | zh_TW |
| dc.subject | 胜肽探針 | zh_TW |
| dc.subject | 類澱粉蛋白質 | zh_TW |
| dc.subject | C9orf72 | zh_TW |
| dc.subject | 甘胺酸-丙胺酸雙肽蛋白質 | zh_TW |
| dc.subject | TDP-43蛋白質 | zh_TW |
| dc.subject | Amyotrophic lateral sclerosis | en |
| dc.subject | TDP-43 | en |
| dc.subject | Glycine-alanine dipeptide repeats | en |
| dc.subject | Peptide probe | en |
| dc.subject | Amyloid | en |
| dc.subject | C9orf72 | en |
| dc.title | 以胜肽探針研究漸凍人症中聚甘胺酸-丙胺酸雙肽蛋白質以及TDP-43蛋白質之病理現象 | zh_TW |
| dc.title | Induction of Glycine-alanine Dipeptide Repeats and TDP-43 Proteinopathies by Peptide Probes for ALS Studies | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.author-orcid | 0000-0003-0101-225X | |
| dc.contributor.advisor-orcid | 陳玉如(0000-0002-3178-6697) | |
| dc.contributor.coadvisor | 黃人則(Jen-Tse Huang) | |
| dc.contributor.coadvisor-orcid | 黃人則(0000-0003-4847-7126) | |
| dc.contributor.oralexamcommittee | 陳儀莊(Hsin-Tsai Liu),黃兆祺(Chih-Yang Tseng),吳昆峯 | |
| dc.subject.keyword | 漸凍人症,C9orf72,類澱粉蛋白質,胜肽探針,甘胺酸-丙胺酸雙肽蛋白質,TDP-43蛋白質, | zh_TW |
| dc.subject.keyword | Amyotrophic lateral sclerosis,C9orf72,Amyloid,Peptide probe,Glycine-alanine dipeptide repeats,TDP-43, | en |
| dc.relation.page | 102 | |
| dc.identifier.doi | 10.6342/NTU202102115 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2021-08-13 | |
| 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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