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研究生:賴慶憶
研究生(外文):Ching-Yi Lai
論文名稱:經感染日本腦炎病毒活化大腦微血管內皮細胞機制探討
論文名稱(外文):Japanese encephalitis virus infection activates brain microvascular endothelial cells
指導教授:蘇鴻麟蘇鴻麟引用關係
口試委員:柯俊良陳甫州陳世順
口試日期:2012-11-23
學位類別:博士
校院名稱:國立中興大學
系所名稱:生命科學系所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2012
畢業學年度:101
語文別:中文
論文頁數:130
中文關鍵詞:日本腦炎病毒內皮細胞淋巴細胞
外文關鍵詞:Japanese encephalitis virusendothelial cellsleukocyte
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現今對於日本腦炎發生淋巴細胞浸潤參與的相關細胞和作用機制仍不清楚。淋巴細胞浸潤到中央神經系統的過程中,腦部微血管內皮細胞層扮演重要的角色。我們發現日本腦炎病毒容易感染大腦微血管內皮細胞,但病毒卻極少在細胞內繁殖複製。所以日本腦炎病毒幾乎不影響內皮細胞存活和內皮細胞層完整性,卻發現有較多淋巴細胞的牽引和貼附到內皮細胞層。實驗結果指出日本腦炎病毒感染的內皮細胞會增加ICAM-1、CINC-1與RANTES的表現,導致淋巴細胞吸引和貼附到內皮細胞層的數目增加。我們進一步研究發現ERK、CPLA2、NF-κB和CREB的磷酸化與活化參與調控內皮細胞ICAM-1、CINC-1和RANTES的表現。由這些證據顯示,內皮細胞層經由日本腦炎病毒感染並不會破壞其完整性;而是誘發更多淋巴細胞的牽引和貼附到內皮細胞層。再加上其他未知的因素造成內皮細胞層完整性破壞,最後導致神經發炎和日本腦炎的現象。

Currently, the underlying mechanisms and the specific cell types associated with Japanese encephalitis-associated leukocyte trafficking are not understood. Brain microvascular endothelial cells represent a functional barrier and could play key roles in leukocyte central nervous system trafficking. We found that cultured brain microvascular endothelial cells were susceptible to Japanese encephalitis virus (JEV) infection with limited amplification. This type of JEV infection had negligible effects on cell viability and barrier integrity. Instead, JEV-infected endothelial cells attracted more leukocytes adhesion onto surfaces and the supernatants promoted chemotaxis of leukocytes. Infection with JEV was found to elicit the elevated production of intercellular adhesion molecule-1, cytokine-induced neutrophil chemoattractant-1, and regulated-upon-activation normal T-cell expressed and secreted, contributing to the aforementioned leukocyte adhesion and chemotaxis. We further demonstrated that extracellular signal-regulated kinase was a key upstream regulator which stimulated extensive endothelial gene induction by up-regulating cytosolic phospholipase A2, NF-κB, and cAMP response element binding protein via signals involving phosphorylation. These data suggest that JEV infection could activate brain microvascular endothelial cells and modify their characteristics without compromising the barrier integrity, making them favorable for the recruitment and adhesion of circulating leukocytes, thereby together with other unidentified barrier disrupting mechanisms contributing to Japanese encephalitis and associated neuroinflammation.

論文目次

中文摘要 I
英文摘要 II
論文目次 IV
圖表目次 IX
附表目次 XIII
縮寫表 XIV
第一章、 緒論 1
第一節、 日本腦炎病毒 1
第二節、 血腦屏障 2
第三節、 病毒與血腦屏障的關係 4
第四節、 研究動機 5
第二章、 材料與方法 7
第一節、 病毒製備與感染 7
一、 病毒增殖 7
二、 病毒溶斑試驗 7
三、 病毒感染 8
第二節、 初代細胞培養 8
一、 初代大腦微血管周細胞 8
二、 初代神經膠細胞 9
三、 初代大腦微血管內皮細胞 9
四、 細胞共培養模式 10
第三節、 實驗分析方法 10
一、 西方墨點法 10
二、 細胞存活度測試(MTS assay) 11
三、 RT-PCR 12
四、 Real time RT-PCR 13
五、 ELISA 13
六、 細胞免疫染色 14
七、 EMSA 14
八、 細胞趨化貼付能力分析 16
九、 細胞電阻阻抗性分析(TEER) 17
十、 共同免疫沉澱法 (Co-immunoprecipitation)17
十一、細胞通透性分析 18
十二、統計分析 18
第三章、 實驗結果 19
第一節、 日本腦炎病毒對體外模擬血腦屏障的影響19
一、初代細胞培養和鑑定 19
二、日本腦炎病毒感染細胞能力分析 19
三、日本腦炎病毒感染造成血腦屏障通透性上升 20四、日本腦炎病毒感染對細胞毒性的影響 20
五、日本腦炎病毒對由內皮細胞模擬之血腦屏障通透性影響 21
六、日本腦炎病毒感染會透過周細胞造成血腦屏障通透性上升 22
七、周細胞是利用分泌一些因子改變內皮細胞層通透性 22
八、日本腦炎病毒感染會透過神經膠細胞造成血腦屏障通透性上升 23
九、神經膠細胞是利用分泌一些因子去改變內皮細胞層的通透性 24
第二節、感染日本腦炎病毒之周細胞對內皮細胞影 25
一、日本腦炎病毒感染對周細胞影響 25
二、感染日本腦炎病毒之周細胞對內皮細胞影響 25
三、日本腦炎病毒感染誘發周細胞產生IL-6分子機
制 26
四、IL-6對內皮細胞影響 28
五、IL-6誘發內皮細胞緊密蛋白降解 29
六、IL-6透過Ubr-1造成ZO-1蛋白降解 31七、IL-6透過JaK-STAT路徑誘發Ubr-1的表現 32
八、IL-6透過JaK-STAT路徑間接調控內皮細胞層通透性 32
第三節、感染日本腦炎病毒之神經膠細胞對內皮細胞影響 33
一、日本腦炎病毒感染對神經膠細胞的影響 33
二、感染日本腦炎病毒之神經膠細胞對內皮細胞影
響 34
三、MMPs對內皮細胞層通透性的影響 34
四、MMPs誘發內皮細胞VEGF 釋放 35
五、VEGF 對內皮細胞的影響 36
第四節、日本腦炎病毒對內皮細胞的影響 36
一、日本腦炎病毒感染誘發內皮細胞發炎表現情形36
二、經感染日本腦炎病毒之內皮細胞對免疫細胞遷移和貼附能力的影響 37
三、誘發內皮細胞發炎表現之分子機制 37
第四章、 討論與結論 40
第五章、 參考文獻 48
第六章、 圖表 76
第七章、 附表 123

圖表目次

圖一、 初代細胞鑑定 82
圖二、 日本腦炎病毒感染能力分析 83
圖三、 日本腦炎病毒對由周細胞、 神經膠細胞、 內皮
細胞模擬之血腦屏障通透性分析 84
圖四、 日本腦炎病毒細胞毒性分析 85
圖五、 日本腦炎病毒對由內皮細胞模擬之血腦屏障通透
性影響分析 86
圖六、 日本腦炎病毒對由周細胞和內皮細胞模擬之血腦
屏障通透性分析分析 87
圖七、 日本腦炎病毒對由周細胞和內皮細胞模擬之血腦
屏障通透性影響分析 88
圖八、 經日本腦炎病毒感染的周細胞對由內皮細胞模擬
之血腦屏障通透性影響分析 89
圖九、 日本腦炎病毒對由神經膠細胞和內皮細胞模擬之
血腦屏障通透性影響分析 90
圖十、 日本腦炎病毒對由神經膠細胞和內皮細胞模擬
之血腦屏障通透性影響分析 91

圖十一、 經日本腦炎病毒感染的神經膠細胞對由內皮
細胞模擬之血腦屏障通透性影響分析 92
圖十二、 日本腦炎病毒誘發周細胞發炎介子蛋白表現
量分析 93
圖十三、 日本腦炎病毒誘發周細胞發炎介子mRNA表現
量分析 95
圖十四、 經感染日本腦炎病毒的周細胞對內皮細胞層
通透性和周邊血液單核球趨化能力分析 96
圖十五、 日本腦炎病毒活化TLR、MAPK路徑誘發周細
胞IL-6表現 98
圖十六、 日本腦炎病毒活化PTK、Ras、PI3K、PKC和cPLA
2路徑誘發周細胞IL-6表現 99
圖十七、 日本腦炎病毒感染活化周細胞MAPK路徑 100
圖十八、 日本腦炎病毒感染活化周細胞轉錄因子分析102
圖十九、 日本腦炎病毒感染周細胞對內皮細胞緊密蛋
白表現分析 103
圖二十、 日本腦炎病毒誘發周細胞產生之IL-6對內皮
細胞緊密蛋白的影響 104
圖二十一、 日本腦炎病毒誘發周細胞產生之IL-6對內

皮細胞緊密蛋白表現量的影響 105
圖二十二、 日本腦炎病毒誘發周細胞產生之IL-6對內
皮細胞緊密mRNA表現量的影響 106
圖二十三、 日本腦炎病毒誘發周細胞產生之IL-6經由
蛋白降解影響內皮細胞緊密蛋白表現量 107
圖二十四、 IL-6透過Ubr-1造成ZO-1蛋白質降解 109
圖二十五、 IL-6透過Ubr-1造成ZO-1蛋白質降解而影
響內皮細胞層通透性 110
圖二十六、 IL-6透過JaK-STAT路徑誘發Ubr-1的表
現 112
圖二十七、 IL-6透過JaK-STAT間接調控內皮細胞層通
透性 114
圖二十八、 日本腦炎病毒感染誘發神經膠細胞MMPs表
現情形 116
圖二十九、 日本腦炎病毒感染神經膠細胞對內皮細胞
之影響 117
圖三十、 日本腦炎病毒感染神經膠細胞對大腦皮質內
皮細胞通透性之影響 119
圖三十一、 內皮細胞處理日本腦炎病毒感染神經膠細

胞之上清液分析VEGF表現情形 120
圖三十二、 日本腦炎病毒感染神經膠細胞之上清液對
大腦皮質內皮細胞之影響 121
圖三十三、 內皮細胞經日本腦炎病毒感染誘發發炎反
應 122
圖三十四、 內皮細胞經日本腦炎病毒感染對免疫細胞
貼附和趨化的影響 123
圖三十五、 日本腦炎病毒感染誘發內皮細胞發炎反應
之路徑 124
圖三十六、 日本腦炎病毒感染誘發內皮細胞發炎反應
之訊息傳遞路徑 126
圖三十七、 日本腦炎病毒感染對細胞的影響 128


附表目次

附表一、 RT-PCR引子 129
附表二、 Real-time PCR引子 130

















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