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研究生:古芙嫚
研究生(外文):Fu-Man Ku
論文名稱:四環黴素誘導陰道鞭毛蟲死亡之分子機制
論文名稱(外文):Molecular mechanism of cell death induced by tetracycline in Trichomonas vaginalis.
指導教授:吳雪霞
指導教授(外文):Hsueh-Hsia Wu
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:醫學檢驗暨生物技術學系所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:104
中文關鍵詞:陰道鞭毛蟲四環黴素細胞凋亡次世代定序
外文關鍵詞:trichomonas vaginalistetracyclineapoptosisnext generation sequencing
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陰道鞭毛蟲為真核單細胞原蟲,寄生於人類的泌尿生殖道,其感染所引起的陰道鞭毛蟲症為最常見的非病毒之性接觸傳染疾病之一。5-Nitroimidazoles為最常用於治療陰道鞭毛蟲症之藥物。然而,根據研究報告顯示,臨床上約2.5-5 %感染陰道鞭毛蟲症患者,對此類藥物產生抗藥性,因此勢必尋找新的且有效之替代藥物。四環黴素為廣泛用於治療革蘭氏陽性與陰性細菌之抗生素,近年來也可見用於治療寄生性原蟲之感染。目前已知四環黴素對部份寄生性原蟲具毒殺之原因為透過粒線體之胞器,但對於缺乏粒線體之陰道鞭毛蟲而言,是否具有毒殺之效果以及作用機制,仍是需要被探討之重要課題。本研究利用次世代定序技術來探討經四環黴素作用下之陰道鞭毛蟲,其基因表現之差異,進而找出可能調控毒殺蟲體之分子機制,並了解其與目前已知之四環素毒殺機制是否相同,以及探討其陰道鞭毛蟲與目前已知死亡方式之相關性。研究結果證實,四環黴素對陰道鞭毛蟲具有毒殺之作用,其蟲體死亡之型態與目前已知細胞凋亡之特徵相似。另外,於四環黴素作用後自噬作用相關蛋白表現受到抑制,因此其可能為藥物毒殺陰道鞭毛蟲的標的之一,於蟲體中扮演促進存活之角色。次世代定序資料分析結果同時顯示,四環黴素促使氨醯tRNA合成酶、糖解路徑、肝醣分解路徑基因表現量均增加,並產生大量丙酮酸代謝產物。轉譯作用相關以及糖解路徑上游之基因表現則受到抑制。另外,氫化體代謝路徑中,參與電子傳遞之基因,於四環黴素作用後其基因表現亦受到抑制。本研究之發現不但於治療陰道鞭毛蟲症上,提供了一新的可作為替代之藥物,可解決目前於治療對5-Nitroimidazoles具有抗性之陰道鞭毛蟲上之困擾。此外,本研究亦建立了一套四環黴素作用後陰道鞭毛蟲次世代定序之參考資料,此平台對未來研究陰道鞭毛蟲藥物之分子機制與藥物發展上,提供了一完整之比對模式。


Trichomonas vaginalis, an ancient extracellular obligate parabasalian flagellate, colonizes the human urogenital tract and causes trichomoniasis, the most common non-viral sexually transmitted disease (STD) in the world. Currently, 5-nitroimidazoles are the only recommended drugs for standard treatment of T. vaginalis infection. However, a marked increase in the development of cross-resistance among the family of 5-nitroimidazole drug has been noted recently and second line drug is still not available. Studies have shown that at least 2.5-5% of clinical cases of trichomoniasis are caused by parasites that are resistant to the above-mentioned drugs. Hence, it is essential to find new and safe agents that are efficacious in the treatment and prevention of refractory tricomoniasis. Tetracycline is abroad-spectrum agent, with activity against both gram-positive and gram-negative bacteria and intracellular chlamydiae, mycoplasmas, and rickettsiae. More recently, tetracycline has been used against eukaryotic protozoan parasites. Some of the parasites treated with tetracycline have tetracycline-susceptible mitochondria, whereas T. vaginalis doesn’t have mitochondria. In organisms without mitochondria, the mechanisms of action and the target sites of the tetracycline are unknown. In the present study, we used next-generation sequencing approach to investigate the differentially expressed genes in T. vaginalis following tetracycline treatment, unraveling the molecular mechanisms of this parasite in response to tetracycline. Here, we demonstrate for the first time that tetracycline has a cytotoxic effect against T. vaginalis. Additionally, a form of cell death with some features resembling apoptosis is present in T. vaginalis following tetracycline treatment. Moreover, we show that tetracycline inhibits the expression of autophagy-related proteins in T. vaginalis, suggesting that targeting autophagy may be one of the cell death mechanisms induced by tetracycline. Our RNA-seq data reveal that genes involved in glycolysis, glycogenolysis and aminoacyl-tRNA synthetase are upregulated, whereas genes associated with translation and the upstream of glycolysis are downregulated upon tetracycline treatment. Collectively, we provide a novel treatment for the 5-nitroimidazole-resistant T. vaignlis strains.Also, we present an in-depth investigation of transcriptomic signatures in T. vaginalis upon tetracycline treatment, hopefully providing a comparative platform for future researches on drug developments in T. vaginalis.


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誌謝 iv
論文摘要 v
Abstract vi
第一章、緖論 1
1、 背景 1
1.1 陰道鞭毛蟲 1
1.1.1 蟲體型態 2
1.1.2 生活史與傳染途徑 3
1.1.3 臨床表徵 4
1.1.4 治療 5
1.2 四環黴素 (Tetracyclines) 6
1.3 細胞凋亡/程序性細胞死亡(Apoptosis / programmed cell death
(PCD))之單細胞原生動物寄生蟲 7
1.4 自噬作用 (Autophagy) 9
1.5 次世代定序 11
1.6 研究目標與動機 12
第二章、材料與方法 13
2.1 陰道鞭毛蟲之培養 13
2.2 四環黴素感受性試驗 14
2.3 四環黴素殘留檢測試劑 14
2.4 陰道鞭毛蟲總量RNA之萃取 15
2.5 反轉錄聚合酶連鎖反應
(Reverse transcription PCR; RT-PCR) 16
2.6 同步定量聚合酶連鎖反應 (Real-time PCR) 17
2.7 Library preparation for RNA-seq 17
2.8 RNA定序資料分析 18
2.9 丙酮酸代謝偵測套組 19
2.10 乳酸代謝偵測套組 20
2.11 ATP偵測套組 21
2.12 細胞凋亡染色 22
2.13 陰道鞭毛蟲蛋白質萃取 22
2.14 SDS-聚丙烯醯胺膠電泳法 (SDS-polyacrylamide gel electrophoresis) 22
2.15 西方墨點法 (Western blot) 23
2.16 雷帕黴素 (Rapamycin)誘導陰道鞭毛蟲產生自噬作用 24
第三章、結果與討論 25
3.1 四環黴素對陰道鞭毛蟲生長之影響 25
3.2 利用RIDASCREEN Tetracycline (R-Biopharm; R3505)酵素免疫
分析定量試劑檢測進入陰道鞭毛蟲體內之四環黴素 27
3.3 四環黴素誘導陰道鞭毛蟲產生類似凋亡或其他形式的程序性
細胞死亡之現象 28
3.4 四環黴素抑制陰道鞭毛蟲自噬作用相關蛋白之表現 30
3.5 自噬作用產生可延緩陰道鞭毛蟲受四環黴素之毒殺 31
3.6 利用次世代定序分析探討在經四環黴素作用之陰道鞭毛蟲, 其基因表現之差異 32
3.7 利用同步定量聚合酶連鎖反應 (quantitative PCR ; qPCR)驗證其
次世代定序資料結果 33
3.8 次世代定序分析資料之比較 34
3.8.1 四環黴素促使氨醯tRNA合成酶 (aminoacyl-tRNA synthetase)
基因表現量上升 35
3.8.2 四環黴素抑制轉譯作用相關之基因表現 36
3.9 於四環黴素作用後陰道鞭毛蟲代謝路徑之變化 37
3.9.1 糖解路徑 37
3.9.2 肝醣分解路徑 38
3.9.3 氫化體代謝途徑 40
3.9.4 胺基酸代謝路徑 42
3.10 四環黴素促使陰道鞭毛蟲大量產生糖解路徑代謝產物丙酮酸 42
3.11 結論 44
第四章、參考文獻 46
圖一、四環黴素影響陰道鞭毛蟲 (ATCC 30236、ATCC 50143)之感受性試驗 53
圖二、以RIDASCREEN Tetracycline酵素免疫分析檢測套組測定陰道鞭毛蟲
四環黴素之殘留 54
圖三、四環黴素作用4小時後誘導陰道鞭毛蟲產生凋亡之現象 55
圖四、四環黴素抑制陰道鞭毛蟲自噬作用相關蛋白TvATG 3與TvATG 8表現 56
圖五、雷帕黴素 (Rapamycin)與四環黴素作用後陰道鞭毛蟲之存活率 57
圖六、利用同步定量聚合酶連鎖反應驗證次世代定序所產生之轉錄體資料 59
圖七、利用同步定量聚合酶連鎖反應驗證次世代定序所產生之轉錄體資料 60
圖八、利用GSEA分析次世代定序所產生之轉錄資料之結果 64
圖九、次世代定序分析資料前100個高表現量基因之生物程序分類 65
圖十、 四環黴素作用下陰道鞭毛蟲之氨醯tRNA合成酶 (aminoacyl-tRNA synthetase) 基因表現量上升 66
圖十一、四環黴素作用下抑制轉譯作用相關基因表現 67
圖十二、四環黴素作用下陰道鞭毛蟲糖解路徑之基因表現 68
圖十三、四環黴素作用下陰道鞭毛蟲肝醣分解路徑之基因表現 69
圖十四、四環黴素作用下陰道鞭毛蟲Hydrogenosome代謝相關基因之表現 70
圖十五、四環黴素作用下陰道鞭毛蟲其胺基酸代謝路徑之基因表現 71
圖十六、四環黴素影響陰道鞭毛蟲糖類分解路徑之代謝產物產量 72
表1、目前已知與細胞凋亡相關之基因,於700 μg/mL四環黴素與未加藥
基因表現量之比較 73
表2、自噬作用相關基因於700 μg/mL四環黴素與未加藥基因表現量之比較 75
表3、次世代定序之統計資料 76
表4、基因引子之序列。於基因體定序資料中,挑選出劑量700 μg/mL四環黴素相較於未加藥作用4小時後,表現量增加之基因,利用qPCR進行驗證 77
表5、基因引子之序列。於次世代定序資料中,挑選出劑量700 μg/mL四環黴素相較於未加藥作用4小時後,表現量下降之基因,利用qPCR進行驗證 78
表6、次世代定序資料經GSEA分析,700 μg/mL四環黴素相較於未加藥 79
作用4小時後,被誘導促使表現量上升之生物路徑 79
表7、次世代定序資料經GSEA分析,700 μg/mL四環黴素相較於未加藥 80
作用4小時後,被誘導促使表現量下降之生物路徑 80
表8、氨醯tRNA合成酶之基因於700 μg/mL四環黴素與未加藥作用4小時後, 基因表現量之比較 81
表9、糖類代謝相關基因於700 μg/mL四環黴素與未加藥作用4小時後, 基因表現量之比較 83
表10、胺基酸代謝相關基因於700 μg/mL四環黴素與未加藥作用4小時後, 基因表現量之比較 88


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