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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳慧文 | |
dc.contributor.author | Chen-Yu Huang | en |
dc.contributor.author | 黃湞鈺 | zh_TW |
dc.date.accessioned | 2021-06-17T09:10:13Z | - |
dc.date.available | 2019-10-17 | |
dc.date.copyright | 2019-10-17 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2019-09-25 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/74915 | - |
dc.description.abstract | II中文摘要中東呼吸症候群冠狀病毒感染症(MiddleEast respiratory syndrome coronavirus;MERS-CoV) 於2012年於中東確定首例,並且目前其疫情仍然持續在中東擴散,截至目前為止,仍未能有批准上市之疫苗可以使用,因此疫苗之研發迫在眉梢。近年來,由於奈米顆粒(Nanoparticle; NP) 具有生物可降解性、穩定性與生物可相容性,奈米顆粒成為疫苗載體研發主要方向之一,為疫苗開發提供了強而有力之遞送系統候選平台。本研究設計了以PLGA裝載有STING促進劑cd-GMP並用MERS-CoV之重組受體結合區(rRBD) 蛋白質作為MERS-CoV的抗原,進行合成仿病毒之奈米顆粒疫苗(rRBD NP) 之製備。於實驗結果中發現,以奈米顆粒形式給予STING 促進劑更容易被樹突細胞攝取、活化、進而產生免疫反應,並且比起肌肉注射給予方式,以皮下注射野生型C57BL/6小鼠給予rRBD NP能更快且持久產生特異性抗體,及有效誘導IgG2a抗體之生成;在細胞免疫方面,顯示rRBD NP能引起具抗原特異性之CD4+與CD8+ T細胞產生IFN-g,及促進記憶型T細胞的生成。進一步將rRBD NP免疫hDPP4基因轉殖小鼠,以致死劑量之MERS-CoV攻毒後,比起未免疫組別,免疫rRBD NP之hDPP4小鼠具有高力價的中和抗體、肺臟病毒含量顯著降低,並有100%的存活率。綜合以上結果表明了rRBD NP做為MERS-CoV疫苗之潛力,並且此仿病毒奈米顆粒載體亦可提供作為其餘疾病疫苗設計之參考。 | zh_TW |
dc.description.abstract | The first caseofMiddle East respiratory syndrome coronavirus (MERS-CoV) was confirmed in Middle East in 2012. To date, there is a continuous outbreak ofMERS-CoV in Middle Eastand no effective prophylactic countermeasure has been developed.Facing the rising threat of MERS-CoV, vaccine development is in urgent need. Recently, nanoparticles (NPs) have become one of the key interests in vaccine development. NPscan be prepared from biodegradable andbiocompatible materials, offering a safe candidate for vaccine delivery. In this study, the synthetic virus-mimetic NPsloaded with a STING (stimulator of interferon genes) agonistwas engeneredand functionalized with recombinant receptor-binding domain (rRBD) protein as a vaccine against MERS-CoV.In contrast to free STING agonist, the STING agonist loaded in NPs is more efficient for dendritic cells uptake and immune responsestimulation.Compared with intramuscular inoculation, rRBD NPs with subcutaneous inoculationinduced strongerand sustainable specific antibody response and also enhanced production of IgG2a antibody in wildtype C57BL/6 mice. For thecellular immunity, rRBD NPs elicited IFN-gproduction which produced by specific CD4+ and CD8+ T cellsand promoted memory T cell generation. Moreover, rRBD NPs vaccination in hDPP4 transgenic mice resulted in reduced lung viral load and high titers of neutralizing antibodiesthat provided 100% protection against a MERS-CoV lethal challenge.Taken together, the rRBD NPs shown potential of MERS-CoV vaccine development and also provide a vaccine platform for other disease vaccine design. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T09:10:13Z (GMT). No. of bitstreams: 1 ntu-107-R04629014-1.pdf: 1929719 bytes, checksum: ac1c9169fc2f46912892cc372b1354dc (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | 序言...I
中文摘要...II Abstract...III 圖目錄...VI 第一章 前言...1 1.1中東呼吸症候群冠狀病毒感染症之流行病學...1 1.2中東呼吸症候群冠狀病毒...1 1.2.1病毒之基因體與蛋白質...1 1.2.2病毒之感染與免疫機制...3 1.4 中東呼吸道症候群之疫苗發展現況...6 1.5 奈米顆粒疫苗應用與發展...8 1.5.1奈米顆粒疫苗載體種類與應用...8 1.5.2 PLGA奈米顆粒之特性與應用...11 1.6 Cyclic di-GMP (cdGMP) 特性與免疫機制...12 1.7 研究動機...13 第二章材料與方法...15 2.1細胞株...15 2.2重組蛋白選殖與表現...15 2.3病毒斑測試...16 2.4 Fast protein liquid chromatography (FPLC) 純化重組蛋白...16 2.5 SDS-PAGE and Western blot...17 2.6奈米顆粒疫苗之製備...18 2.7 High Performance Liquid Chromatography (HPLC) 確認cdGMP包覆率...20 2.8蛋白質定量...21 2.9 Dynamic light scattering (DLS) 檢測奈米顆粒特性...21 2.10負染色、免疫金染色與穿透式電子顯微鏡(TEM) 分析...22 2.11奈米顆粒遞送之細胞試驗...22 2.12奈米顆粒遞送之動物試驗...24 2.13冷凍切片與染色...24 2.14野生型小鼠免疫試驗...25 2.15測定特異性與IgG分型之抗體效價...25 2.16胞內細胞激素染色(ICS) 與細胞表面標記染色(surface staining)...26 2.17 Antibody-dependent cell-mediated cytotoxicity (ADCC)...27 2.18基因轉殖小鼠之免疫與攻毒試驗...27 2.19血清中和試驗...28 第三章結果...29 3.1重組蛋白質抗原之生產、純化與確認...29 3.2 cdGMP NP之特性分析...29 3.3 cdGMP NP於樹突細胞中引發之免疫反應...30 3.4cdGMP NP 免疫小鼠後之局部免疫反應...30 3.5rRBD NP之特性分析...31 3.6以rRBD NP或不同抗原之奈米顆粒疫苗在小鼠中誘發特異性抗體產生...32 3.7以rRBD NP或不同抗原之奈米顆粒疫苗在小鼠中誘發中和抗體生成...34 3.8評估rRBD NP是否在小鼠中誘導Antibody-dependent cell-mediated cytotoxicity (ADCC)...34 3.9以rRBD NP在小鼠中誘發特異性細胞免疫反應...35 3.10奈米顆粒疫苗免疫基因轉殖老鼠之保護試驗...36 第四章討論...37 第五章圖...42 第六章參考文獻...62 | |
dc.language.iso | zh-TW | |
dc.title | 以裝載STING促進劑之仿病毒奈米顆粒作為中東呼吸症候群冠狀病毒感染症之疫苗 | zh_TW |
dc.title | A STING Agonist-loaded Viromimetic Nanoparticle for Middle East Respiratory Syndrome Coronavirus Vaccine | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-1 | |
dc.description.degree | 碩士 | |
dc.contributor.coadvisor | 胡哲銘 | |
dc.contributor.oralexamcommittee | 莊榮輝,林俊宏,張世宗 | |
dc.subject.keyword | 中東呼吸症候群冠狀病毒感染症,PLGA,STING促進劑,RBD,奈米疫苗, | zh_TW |
dc.subject.keyword | MERS-CoV,PLGA,STING agonist,RBD,nanoparticle vaccine, | en |
dc.relation.page | 71 | |
dc.identifier.doi | 10.6342/NTU201802369 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2019-09-26 | |
dc.contributor.author-college | 獸醫專業學院 | zh_TW |
dc.contributor.author-dept | 獸醫學研究所 | zh_TW |
顯示於系所單位: | 獸醫學系 |
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