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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 方俊民(Jim-Min Fang) | |
dc.contributor.author | Ming-Cheng Chen | en |
dc.contributor.author | 陳明正 | zh_TW |
dc.date.accessioned | 2021-06-17T00:33:09Z | - |
dc.date.available | 2017-02-01 | |
dc.date.copyright | 2012-02-21 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2012-02-08 | |
dc.identifier.citation | 1. Kindt, T. J.; Goldsby, R. A.; Osborne, B. A. 2007, W. H. Freeman and Company. Kuby Immunology.
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Mastroeni, P.; Chabalgoity, J A.; Dunstan, S. J.; Maskel , D. J.; Dougan, G. Vet. J. 2000, 161, 132–164. Salmonella: immune responses and vaccines. 45. Levine, M. M.; Ferreccio, C.; Black, R. E.; Tacket, C. O.; Germanier, R. Rev. Infect. Dis. 1989, 11, Suppl 3: S552–567. Progress in vaccines against typhoid fever. 46. Ding, H. F.; Nakoneczna, I.; Hsu, H. S. J. Med. Microbiol. 1990, 31, 95–101. Protective immunity induced in mice by detoxified Salmonella lipopolysaccharide. 47. Meenakshi, M.; Bakshi, C. S.; Butchaiah, G.; Bansal, M. P.; Siddiqui, M. Z.; Singh, V. P. Vet. Res. Commun. 1999, 23, 81–90. Adjuvanted outer membrane protein vaccine protests poultry against infection with Salmonella enteritidis. 48. Watson, D. C.; Robbins, J. B.; Szu, S. C. Infect. Immun. 1992, 60, 4679–4686. Protection of mice against Salmonella typhimurium with an O-specific polysaccharide-protein conjugate vaccine. 49. (a) Konadu, E.; Shiloach, J.; Bryla, D. A.; Robbins, J. B.; Szu, S. C. Infect. Immun. 1996, 64, 2709–2715. Synthesis, characterization, and immunological properties in mice of conjugates composed of detoxified lipopolysaccharide of Salmonella paratyphi A bound to tetanus toxoid, with emphasis on the role of O acetyls. (b) Konadu, E. Y.; Lin, F. Y.; Ho, V. A.; Thuy, N. T.; Van Bay, P.; Thanh, T. C.; Khiem, H. B.; Trach, D. D.; Karpas, A. B.; Li, J.; Bryla, D. A.; Robbins, J. B.; Szu, S. C. Infect. Immun. 2000, 68, 1529–1534. Phase 1 and phase 2 studies of Salmonella enterica serovar paratyphi a O-specific polysaccharide-tetanus toxoid conjugates in adults, teenagers, and 2- to 4- year-old children in Vietnam. 50. Bock, K.; Meldal, M.; Bundle, D. R.; Iversen, T.; Pinto, B. M.; Garegg, P. J.; Kvanström, I.; Norberg, T.; Lindberg, A. A.; Svenson, S. B. Carbohydr. Res. 1984, 15, 35–53. The conformation of Salmonella O-antigenic oligosaccharides of serogroups A, B, and D1 inferred from 1H- and 13C-nuclear magnetic resonance spectroscopy. 51. (a) Jörbeck, H. 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Synthesis, characterization, and immunogenicity in mice of Shigella sonnei O-specific oligosaccharide-core-protein conjugates. (b) Kubler-Kielb, J.; Vinogradov, E.; Mocca, C.; Pozsgay, V.; Coxon, B.; Robbins, J. B.; Schneerson, R.; Carbohydr. Res. 2010, 345, 1600–1608. Immunochemical studies of Shigella flexneri 2a and 6, and Shigella dysenteriae type 1 O-specific polysaccharide-core fragments and their protein conjugates as vaccine candidates. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/66383 | - |
dc.description.abstract | 利用存在於病原及癌細胞表面具特異性的醣分子做為抗原,進而誘發抗體達到治療效果,已成為疫苗研究中的新策略。而在醣疫苗的開發過程中,一個有效方便的醣聯抗原合成方式,便成了具關鍵性要素的課題。對於革蘭氏陰性菌而言,連接細胞壁上O-specific polysaccharide與lipid A之間具高度保守性的Kdo (3-deoxy-D-manno-octulosonic acid),是一個極具吸引力的抗原衍生化標的,除了因為其存在於各種革蘭氏陰性菌的O-specific polysaccharide末端,由其衍生的醣聯抗原也能夠保留細菌脂多醣的抗原性,然而,目前仍沒有一個有效方法能藉由針對性的修飾Kdo,進而與攜帶蛋白連接合成具細菌特異性的醣聯蛋白抗原。
在我們的研究中,首先試圖由Kdo與鄰苯二胺連接體出發合成醣聯蛋白抗原,在以大腸桿菌脂多醣為模型的實驗裡,我們成功合成了醣聯蛋白抗原,並藉由小鼠實驗證明其抗原性。另一方面,沙門氏鼠傷寒桿菌的感染一直是嚴重的全球公衛問題,雖然經過長期的研究,目前仍然沒有有效疫苗可供運用。因此,在研究的第二部份,試圖利用我們開發的方法,應用到沙門氏鼠傷寒桿菌脂多醣的醣聯蛋白抗原合成。經過具抗原性脂多醣片段的純化與鑑定,我們已接續完成醣聯蛋白抗原的合成,而相關的小鼠免疫實驗正在進行中。未來這個方法或許可廣泛應用於革蘭氏陰性菌的醣疫苗開發,也希望能幫助沙門氏鼠傷寒桿菌的疫苗研究。 | zh_TW |
dc.description.abstract | The synthesis of glycan conjugate is the critical issue in the glycan vaccinology. Traditionally, an immunogen is composed of protein or peptide fragments, but using the highly conservative glycan on the surface of pathogen (e.g. lipopolysaccharide, LPS) or tumor cell (e.g. Global H) as the immunogen has illuminated another direction in vaccine research. For Gram-negative bacteria, the 3-deoxy-D-manno-octulosonic acid (Kdo) is an attractive target for glycan immunogen synthesis. It is highly conservatively at the terminal of O-specific polysaccharide of LPS, and the derivatization from Kdo retains the immunogenicity for immune cell recognition. However, there is no efficient method has been developed for the synthesis of Kdo-derivatized glycan conjugates.
In our study, a new method for the construction of glycan conjugate from Kdo is developed. This method is site-specific and reacts under mild acid conditions between O-specific polysaccharide and diamine linker. Utilizing the LPS of E. coli as a model, we have successfully synthesized the glycan conjugates and evaluated its immunogenicity. In another part, we target Salmonella typhimurium, which is a highly pathogenic Gram-negative bacterium worldwide. After more than thirty years’ investigation, there still lacks an efficient vaccine for S. typhimurium prevention. To further apply our conjugation method, the glycan immunogens were synthesized from the immunogenic fractions of LPS in S. typhimurium. The corresponding immunization experiment is in progress. Our strategy might promise a new approach for the development of S. typhimurium glycan vaccine. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T00:33:09Z (GMT). No. of bitstreams: 1 ntu-100-R98223203-1.pdf: 2842207 bytes, checksum: fd23e361ecd29420ffbd7e44d346e0ec (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | Acknowledgements I
Abstract in Chinese II Abstract in English III Table of Contents V Index of Figures XI Index of Schemes XIV Index of Tables XVI Abbreviations XVII Chapter 1. Introduction 1 1.1 Introduction of vaccine 1 1.2 Introduction of LPS 4 1.2.1 O-specific polysaccharide 7 1.2.2 Core polysaccharide 7 1.2.3 Lipid A 9 1.3 Development of glycan vaccine 10 1.3.1 Anti-bacteria 11 1.3.2 Anti-tumor 12 1.3.3 Anti-virus 13 1.4 Immunology of glycan immunogen 14 1.5 Methods for glycan vaccine synthesis 16 1.5.1 Reductive amination 18 1.5.2 Oxime formation 21 1.5.3 Random CNBr activation 22 1.5.4 Carboxylic acid derivatization 23 1.6 Factors for the immunogenicity of glycan vaccines 24 1.6.1 Carrier protein 24 1.6.2 Linker 25 1.6.3 Glycan immunogen 26 1.7 Role of Kdo in bacteria 27 1.8 Introduction of Salmonella 28 1.8.1 Classification 29 1.8.2 Epidemiology and pathogenesis 31 1.8.3 Clinical manifestation and treatment 32 1.8.4 Vaccines 33 1.9 Development of S. typhimurium vaccine 35 1.10 Outline of my research 38 Chapter 2. Results and Discussion 39 2.1 Previous researches in our laboratory 39 2.2 Research strategy 41 2.3 Design and synthesis of diamine linkers 43 2.4 Synthesis of E. coli glycan immunogen and its immunogenicity 45 2.4.1 Detoxification of LPS 45 2.4.2 Synthesis of glycan–carrier protein conjugates 49 2.4.3 Identification of the glycan–carrier protein conjugates 56 2.4.4 Immunization experiments 58 2.5 Synthesis of S. typhimurium glycan immunogen and study of its immunogenicity 60 2.5.1 Detoxification of LPS 60 2.5.2 Synthesis and identification of glycan–carrier protein conjugates 61 2.5.3 Immunization and challenging experiments 64 2.5.4 Modified strategy in the design of anti- S. typhimurium vaccine 67 2.5.5 Purification of LFLPS by size exclusion chromatography 68 2.5.6 Determine the immunogenic fractions by anti-S. typhimurium serum 71 2.5.7 Synthesis of LFLPS–carrier protein conjugates by purified glycan 72 2.6 Conclusions 74 Chapter 3. Experimental Section 77 3.1 General Part 77 3.2 Synthetic procedures and characterization of compounds 78 3.3 Preparation of lipid-A free polysaccharide (LFLPS) 81 3.4 Conjugation of LFLPS with diamine linker 3 82 3.5 Conjugation of LFLPS–diamine conjugate with di-OSu linker 4 82 3.6 Modification of the lysine residues of BSA by MBS or sulfo-MBS 83 3.7 Modification of the lysine residues of OVA by MBS or sulfo-MBS 83 3.8 Conjugation of the thiol-derived LFLPS with maleimide-activated carrier protein 84 3.9 Culture and purification of LPS from S. typhimurium 85 3.10 LPS–induced human macrophage cell line assay 87 3.11 Separation of LFLPS from S. typhimurium by size exclusion gel filtration 88 3.12 Phenol–sulfuric acid assay 88 3.13 Coomassie brilliant blue assay 88 3.14 Immunogenicity test of LFLPS from S. typhimurium 89 3.15 Ellman’s assay 90 3.16 SDS-PAGE 90 3.17 Mice immunization experiment 91 3.18 Serum antibody titer test 92 3.19 Bacteria challenging test 92 References 93 Appendix: 1H and 13C NMR spectra 105 | |
dc.language.iso | en | |
dc.title | 抗鼠傷寒沙門氏菌之脂多醣醣疫苗開發 | zh_TW |
dc.title | Synthesis, characterization, and immunogenicity of O-specific polysaccharide based glycan vaccine against Salmonella typhimurium | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 邱政洵(Cheng-Hsun Chiu),羅禮強(Lee-Chiang Lo),楊文彬(Wen-Bin Yang) | |
dc.subject.keyword | 沙門氏鼠傷寒桿菌,脂多醣,鄰苯二胺,醣疫苗, | zh_TW |
dc.subject.keyword | glycan vaccine,kdo,lipopolysaccharide,o-phenylenediamines,Salmonella typhimurium, | en |
dc.relation.page | 113 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2012-02-09 | |
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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