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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張明富 | zh_TW |
| dc.contributor.author | 張博皓 | zh_TW |
| dc.contributor.author | Bo-Hau Chang | en |
| dc.date.accessioned | 2021-06-17T03:37:08Z | - |
| dc.date.available | 2023-12-07 | - |
| dc.date.copyright | 2018-03-29 | - |
| dc.date.issued | 2018 | - |
| dc.date.submitted | 2002-01-01 | - |
| dc.identifier.citation | 1 Zaki, Ali Moh, Boheemen, Sander van, Bestebroer, Theo M., Osterhaus, Albert D.M.E. & Fouchier, Ron A.M. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med. 367, 1814-20 (2012).
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/69980 | - |
| dc.description.abstract | 中東呼吸症候群冠狀病毒(Middle East respiratory syndrome coronavirus, MERS-CoV)係2012年首次出現於沙烏地阿拉伯地區之新興病毒，目前已確認為中東呼吸症候群(Middle East respiratory syndrome, MERS)之病原體。隨著前往中東的旅遊人數增加，此病毒逐漸傳播至其他地區如北美洲、歐洲、非洲及亞洲。截至2017年12月已有2123名確診病例，其中740名病患已經死亡，死亡率約35%，遠高於2003年出現之嚴重急性呼吸症候群(severe acute respiratory syndrome, SARS)的9.6%。MERS-CoV係一正向單股RNA病毒，結構蛋白質包含spike、envelope、membrane及nucleocapsid蛋白質。目前已知MERS-CoV係透過與人類細胞表面之受體dipeptidyl peptidase 4 (hDPP4)結合並入侵宿主細胞，且MERS-CoV感染細胞株及普通狨(common marmoset)時會造成FGF-2及SMAD7的表現量上升，與導致細胞凋亡(apoptosis)有關，然而對於其機轉仍舊不明瞭。故本研究欲探討MERS-CoV係透過何種訊息傳遞路徑誘導FGF-2及SMAD7之表現。利用重組桿狀病毒於昆蟲細胞中表現含受體結合區之MERS-CoV棘蛋白S1次單元，以人胚胎肺纖維母細胞株HFL-1作為實驗平台。結果發現當加入MERS-CoV S1與HFL-1細胞共同培養時，FGF-2的mRNA及蛋白質表現量皆有上升，然而SMAD7之表現則不受影響。此外MERS-CoV S1可促進ERK1/2及JNK1/2之磷酸化，而p38之磷酸化則是下降。若以專一性抑制ERK1/2磷酸化之MEK抑制劑PD98059處理細胞後則MERS-CoVS1蛋白質無法誘導FGF-2之表現，由此可知MERS-CoVS1可能透過ERK1/2之路徑促進FGF-2之表現。另外，預先以DPP4抗體干擾MERS-CoV S1與DPP4之結合時，仍無法抑制MERS-CoV S1誘導FGF-2之能力，故推測MERS-CoV S1可能係透過未知的細胞表面蛋白質誘導ERK1/2所介導之FGF-2蛋白質表現增加。本研究成功找到MERS-CoV透過其棘蛋白S1次單元誘導FGF-2蛋白質表現之可能訊息傳遞路徑。 | zh_TW |
| dc.description.abstract | Middle East respiratory syndrome coronavirus (MERS-CoV) is an emergent zoonotic betacoronavirus which was initially identified in the Kingdom of Saudi Arabia in September 2012. With the increase of travelers to the Middle East, the transmission of MERS-CoV has been reported from countries in North America, Europe, Africa and Asia. To date, MERS-CoV has caused 2123 laboratory confirmed cases with a mortality rate around 35%, which is much higher than the mortality rate of 9.6% caused by severe acute respiratory syndrome coronavirus (SARS-CoV). MERS-CoV is a positive single-strand RNA virus with structural proteins including spike, membrane, envelope and nucleocapsid proteins. The spike (S) protein of MERS-CoV mediates the viral entry into target cells through its specific interaction with human dipeptidyl peptidase 4 (hDPP4) on the cell membrane. MERS-CoV infection can upregulate the expression of FGF-2 and SMAD7 and induce apoptosis in cell models and common marmoset through unknown mechanisms. This study aims to shed light on the mechanism of upregulation of FGF-2 and SMAD7 during MERS-CoV infection. MERS-CoV spike S1 subunit, which contains receptor binding domain was produced by baculovirus expression vector system. Secreted MERS-CoV S1 subunit was purified and incubated with MERS-CoV-susceptible HFL-1 human lung fibroblast cells. Quantitative reverse transcription polymerase chain reaction and Western blot analysis demonstrated increased expression levels of mRNA and protein of FGF-2, respectively, but not SMAD7. Further studies demonstrated that MERS-CoV S1 subunit enhanced phosphorylation of ERK1/2 and JNK1/2, but reduced the phosphorylation of p38 MAPK. In addition, pretreatment of HFL-1 with antibodies specific to DPP4 could not abolish the upregulation of FGF-2 induced by MERS-CoV S1 subunit. These results suggested that MERS-CoV S1 subunit induced upregulation of FGF-2 in an hDPP4-independent manner. In conclusion, this study successfully identified the possible mechanism of MERS-CoV-induced FGF-2 upregulation through the viral spike protein. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T03:37:08Z (GMT). No. of bitstreams: 1 ntu-107-R04442018-1.pdf: 2785620 bytes, checksum: 34c938d3a6100b2e96e655f336e09bc8 (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 摘要 I
Abstract II 第一章、 緒論 1 1. MERS之相關研究 1 1.1. 中東呼吸症候群 (Middle East respiratory syndrome, MERS) 1 1.2. 中東呼吸症候群冠狀病毒(MERS coronavirus, MERS-CoV) 3 2. Dipeptidyl peptidase 4 (DPP4, CD26)之相關研究 8 2.1. 高度醣化區(highly glycosylated region)： 8 2.2. 富半胱胺酸區(cysteine rich region)： 9 2.3. 催化區(catalytic region)： 9 3. Fibroblast growth factor-2 (FGF-2)之相關研究： 10 第二章、 研究目的 12 第三章、 材料來源 13 1. 藥品： 13 2. 抗體： 14 2.1. Primary antibody: 14 2.2. Secondary antibody: 15 3. 細胞培養液及試劑 15 4. 細胞株 15 4.1. Sf9 細胞株 15 4.2. BTI-TN-5B1-4 (Hi Five)細胞株 15 4.3. HFL1細胞株 16 5. 套組試劑 16 6. 引子 16 第四章、 實驗方法 17 1. 細胞株繼代培養 17 1.1. 貼附細胞(adhesion cell)之培養 17 1.2. 懸浮細胞(suspension cell)之培養 17 2. 桿狀病毒表現載體系統 (Baculovirus Expression Vector System, BEVS) 18 2.1. 病毒增殖(virus amplification) 18 2.2. 重組蛋白質表現 18 3. 細胞內RNA之收集 19 4. 反轉錄聚合酶反應 19 5. 即時聚合酶鏈鎖反應(real-time PCR, qPCR) 19 6. 細胞全蛋白質收集 20 7. 蛋白質定量 20 8. 正十二烷硫酸鈉-聚丙烯醯胺膠體電泳 (SDS-polyacrylamide gel electrophoresis, SDS-PAGE) 20 9. 西方墨點法(Western blot analysis) 22 9.1. 蛋白質轉漬(protein transfer) 22 9.2. 以抗體偵測PVDF上的抗原 22 9.3. 呈色 22 10. 銀染 23 第五章、 實驗結果 25 1. 利用桿狀病毒表現載體系統(BEVS)在昆蟲細胞中表現MERS-CoV棘蛋白之S1次單元 25 2. 觀察MERS-CoV S1蛋白質誘導FGF-2及SMAD7表現之情形 26 2.1. 利用即時聚合酶鏈鎖反應觀察FGF-2及SMAD7之mRNA表現量是否受到MERS-CoV S1蛋白質的影響 26 2.2. 利用西方墨點法觀察FGF-2蛋白質的表現是否受到MERS-CoV S1蛋白質的影響 27 3. MERS-CoV S1蛋白質可活化細胞中MAPK之訊息傳遞路徑 28 4. MERS-CoV S1蛋白質透過活化ERK1/2使FGF-2表現量上升 29 5. DPP4可能未參與MERS-CoV S1蛋白質誘導FGF-2表現之訊息傳遞路徑 29 第六章、 討論 31 1. MERS-CoV S1蛋白質以不同昆蟲細胞株表現之差異性 31 2. p38 MAPK之去磷酸化 32 3. MERS-CoV S1蛋白質與細胞凋亡 34 4. FGF-2與纖維化(fibrosis)的關係 34 第七章、 圖表 36 圖一、 以昆蟲細胞表現系統生產及純化MERS-CoV S1蛋白質 36 圖二、 MERS-CoV S1蛋白質誘導FGF-2之mRNA表現 37 圖三、 MERS-CoV S1誘導FGF-2之蛋白質表現量 38 圖四、 MAPK路徑在MERS-CoV S1蛋白質與HFL-1細胞培養下之調控情形 39 圖五、 ERK抑制劑對於MERS-CoV S1誘導FGF-2蛋白質表現之影響 40 圖六、 Anti-DPP4抗體對MERS-CoV S1誘導FGF-2表現之影響 41 圖七、 MERS-CoV S1誘導FGF-2表現之模式圖 42 第八章、 附錄 43 附圖一、 以Sf9及Hi Five細胞表現MERS-CoV S1之情形 43 附圖二、 MERS-CoV S1蛋白誘導apoptotsis之情形 44 附圖三、 HFL-1細胞不同時間之飢餓處理下MAPK磷酸化之情形 45 附圖四、 MERS-CoV之結構及其棘蛋白之示意圖 46 附圖五、 MERS-CoV之生活史 47 第九章、 參考文獻 48 | - |
| dc.language.iso | zh_TW | - |
| dc.subject | 成纖維細胞生長因子-2 | zh_TW |
| dc.subject | MAPK途徑 | zh_TW |
| dc.subject | 二?基??-4 | zh_TW |
| dc.subject | 成纖維細胞生長因子-2 | zh_TW |
| dc.subject | 中東呼吸症候群冠狀病毒棘蛋白 | zh_TW |
| dc.subject | MAPK途徑 | zh_TW |
| dc.subject | 二?基??-4 | zh_TW |
| dc.subject | 中東呼吸症候群冠狀病毒棘蛋白 | zh_TW |
| dc.subject | MERS-CoV spike protein | en |
| dc.subject | MAPK pathway | en |
| dc.subject | DPP4 | en |
| dc.subject | FGF-2 | en |
| dc.subject | MERS-CoV spike protein | en |
| dc.subject | MAPK pathway | en |
| dc.subject | DPP4 | en |
| dc.subject | FGF-2 | en |
| dc.title | 中東呼吸症候群冠狀病毒棘蛋白正調控生長因子FGF-2基因之機轉 | zh_TW |
| dc.title | Mechanisms of MERS-CoV spike protein involved in the regulation of FGF-2 gene | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 106-1 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 劉旻禕;李明學;伍安怡 | zh_TW |
| dc.contributor.oralexamcommittee | ;; | en |
| dc.subject.keyword | 中東呼吸症候群冠狀病毒棘蛋白,成纖維細胞生長因子-2,二?基??-4,MAPK途徑, | zh_TW |
| dc.subject.keyword | MERS-CoV spike protein,FGF-2,DPP4,MAPK pathway, | en |
| dc.relation.page | 63 | - |
| dc.identifier.doi | 10.6342/NTU201800196 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2018-02-12 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | - |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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