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研究生:林品宏
研究生(外文):Pin-HungLin
論文名稱:抑制Lysine-specific Demethylase 1的活性降低單純疱疹病毒在小鼠的感染
論文名稱(外文):Suppression of Lysine-specific Demethylase 1 Activity Reduces Herpes Simplex Virus Infection in Mice
指導教授:陳舜華陳舜華引用關係
指導教授(外文):Shun-Hua Chen
學位類別:碩士
校院名稱:國立成功大學
系所名稱:微生物及免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:49
中文關鍵詞:單純疱疹病毒LSD1TCP
外文關鍵詞:Herpes simplex virusLSD1TCP
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單純疱疹病毒感染眼睛會造成疱疹性角膜炎,感染中樞神經系統會造成致死性腦炎。臨床上使用acyclovir來治療疱疹病毒感染的病人,但是常常有抗acyclovir病毒的發生,尤其是在免疫缺陷的病人。在感染期間,疱疹病毒可以藉由招集lysine-specific demethylase-1 (LSD1) 將病毒立即性早期基因啟動子上的組蛋白去甲基化,進而促進病毒的複製。除此之外,在細胞 (in vitro) 的實驗中發現抑制LSD1可以降低疱疹病毒的複製。然而,抑制LSD1的活性,是否可以降低疱疹病毒在動物活體的感染及疾病仍未被探討。在論文中我利用細胞實驗和小鼠感染模式去探討這個問題。In vitro結果顯示,在小鼠和人類的細胞株中,給予LSD1抑制劑,tranylcypromine (TCP),降低了野生型病毒和抗acyclovir病毒的複製。此外在小鼠活體 (in vivo) 結果顯示,感染前和感染後給予感染小鼠TCP治療,都能降低抗acyclovir病毒在小鼠眼睛中的病毒量。在疱疹性腦炎的小鼠模式中發現,TCP治療顯著的降低感染小鼠的死亡率達45%,以及降低在感染小鼠的眼睛、三叉神經和腦中的病毒量。在疱疹性角膜炎的小鼠模式中,我們發現TCP的治療,可以降低眼睛的疾病嚴重程度、血管新生和病毒量。此外,在潛伏感染小鼠經由高溫處理來誘導病毒復發的動物模式中,我們發現TCP治療降低病毒從小鼠的三叉神經中復發的比例。總結來說,這些結果顯示抑制LSD1,可以降低疱疹病毒在小鼠的複製、疾病的嚴重程度及復發。在將來LSD1的抑制劑可以當成另類的治療,尤其是治療抗藥性病毒感染的病人。
Herpes simplex virus (HSV) infection causes stromal keratitis (HSK) and fatal encephalitis (HSE). Acyclovir is used to treat patients, but the emergence of acyclovir-resistant virus frequently occurs, especially in immunocompromised patients who are highly susceptible to HSV infection. During infection, HSV can facilitate viral replication by recruiting lysine-specific demethylase-1 (LSD1) to demethylate histones bound on promoters of viral immediate-early genes. Inhibition of LSD1 has been shown to suppress HSV replication in vitro. However, it remains unclear whether inhibition of LSD1 could reduce HSV infection and diseases in vivo. To address this issue, we used in vitro studies and more importantly, murine infection models. Our in vitro results showed that treatment with a LSD1 inhibitor, tranylcypromine (TCP), reduced the replication of wild type and acyclovir-resistant HSV-1 in both mouse and human cell lines. In addition, in vivo results revealed that in the mouse eye infected with acyclovir-resistant HSV-1, treatment of TCP before or after infection reduced viral titers. In mice with HSE, TCP treatment significantly decreased the death rate by 45% and viral loads in the eye, trigeminal ganglion, and brain. In mice with HSK, TCP treatment diminished the corneal disease and angiogenesis as well as the eye viral titer. In addition, in latently infected mice subjected to hyperthermia to induce viral reactivation, TCP treatment suppressed HSV-1 reactivation from the mouse trigeminal ganglion. Collectively, these results show that inhibition of LSD1 reduces HSV infection and diseases in mice and suggest that the LSD1 inhibitor could be used as an alternative therapy, especially for acyclovir-resistant HSV-1 in patients.
中文摘要 1
英文摘要 2
致謝 3
目錄 5
圖目錄 6
緒論 7
實驗材料與方法 14
結果 20
討論 27
參考文獻 31
附圖 36
附錄 49

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