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系統識別號 U0026-1501201417054500
論文名稱(中文) 抗凋亡家族蛋白Bcl-2與Bcl-xL對野田病毒所誘導魚類宿主細胞死亡與自噬作用之研究
論文名稱(英文) The roles of anti-apoptotic family membranes Bcl-2 and Bcl-xL on betanodavirus-induced host cell death and autophagy in fish cells
校院名稱 成功大學
系所名稱(中) 生物科技研究所
系所名稱(英) Institute of Biotechnology
學年度 102
學期 1
出版年 103
研究生(中文) 李昂融
研究生(英文) Ang-Jung Lee
學號 L66004062
學位類別 碩士
語文別 中文
論文頁數 124頁
口試委員 指導教授-洪健睿
口試委員-劉宏仁
召集委員-劉校生
口試委員-黃玲惠
中文關鍵字 神經壞死病毒  石班魚  Bcl-2家族蛋白質  活性氧分子  自噬作用  抗氧化酵素  病毒複製  細胞死亡 
英文關鍵字 Betanodavirus (RGNNV)  Bcl-2 family proteins  reactive oxygen species (ROS)  autophagy  antioxidants  viral replication  cell death 
學科別分類
中文摘要 自噬現象是一種細胞在面對壓力時所產生的代謝途徑,藉此將錯誤摺疊蛋白以及老舊或損壞胞器分解掉,以供給細胞合成新胞器或作為其他用途。若細胞面臨壓力或受病原菌入侵,也會活化此現象。我們已證實,對於會感染石斑魚幼苗與多數經濟魚種的神經壞死病毒(RGNNV),感染後會造成粒線體損傷導致細胞死亡,並伴隨Bcl-2家族蛋白Bcl-2與Bcl-xL表現量下降。然而,RGNNV感染也會刺激細胞內O2-與H2O2的產生,其中O2-累積與自噬作用的誘導過程有關。Bcl-2與Bcl-xL是否參予在RGNNV所誘發的自噬作用與細胞死亡調控中,目前尚未明瞭。
本論文利用穩定表現Bcl-2或Bcl-xL之細胞株,來探討此現象。結果顯示,在GF-1細胞中表現Bcl-2或Bcl-xL,能減緩RGNNV誘導的粒線體膜電位喪失(MMP loss)、細胞死亡、減少自噬作用指標蛋白LC3-II的轉換與病毒的複製。有趣的是,穩定表現Bcl-2或Bcl-xL能減少病毒感染刺激細胞內O2-與H2O2的產生。反之,利用Bcl-2抑制劑ABT-199,會增加病毒感染後,細胞內O2-的產生。接著,分析Bcl-2與Bcl-xL是如何影響ROS的產生。結果顯示,細胞內表現Bcl-2或Bcl-xL,會增加抗氧化酵素MnSOD表現量,抗氧化酵素增加可能與ROS的減少有關。最後發現,在沒有病毒感染情況下,利用ROS促進劑tBHQ刺激細胞內ROS產生,穩定表現Bcl-2或Bcl-xL也能減少細胞內ROS生成。總結以上結果,可以說明Bcl-2或Bcl-xL可透過調節細胞內ROS,來抑制病毒感染誘發由粒線體主導的細胞死亡與自噬作用。
英文摘要 Autophagy is a metabolic process to remove damaged protein or organells for recycling when cells were under the stresses. The autophagic response can be activated under environmental stress conditions and various pathogen infections. Here, betanodavirus (RGNNV), a pathogen that causes infectious disease in larva of grouper fish and in other economic fishes. Previously, we found that RGNNV infection can induce host mitochondria-mediated cell death and downregulate the Bcl-2 family proteins Bcl-2 and Bcl-xL. Furthermore, betanodavirus infection also increases O2- and H2O2 production, and that accumulation of O2- is essential for autophagy. But, whether they can regulate RGNNV-induced autophagic response is still unknown. And how to links to cell death is also unclear.
In this study, we demonstrated that both Bcl-2 and Bcl-xL overexpression in GF-1 cells can prevent RGNNV-induced mitochondrial membrane potential loss(MMP loss) and cell death. Then, Bcl-2 family members also can modulate the RGNNV-induced autophagosome process for decreasing viral replication. Interestingly, overexpression of Bcl-2 family proteins also decreases intracellular ROS(O2- and H2O2) production with betanodavirus infection in fish cells. On the contrary, when Bcl-2 was inhibited by ABT-199, Bcl-2 inhibitor, the virus-induced O2- production were enhanced.
Furthermore, we still don’t know whether Bcl-2 family proteins can regulate autophgic response through modulation of ROS production. Our results showed, Bcl-2 and Bcl-xL overexpression can up-regulate anti-oxidant enzymes such as Mn SOD、catalase, which are correlated to decrease of ROS production. Finally, in Bcl-2 or Bcl-xL overexpression cells, treatment of ROS inducer tBHQ showed that the formation of O2- and H2O2 was reduced. Taken together, these results showed that Bcl-2 and Bcl-xL proteins can regulate RGNNV-induced host mitochondrial-mediated cell death and autophagy process via modulation of ROS production by oxidative stress response.
論文目次 目錄

摘要 I
Abstract II
誌謝 III
目錄 IV
圖表目錄 IX
附錄目錄 XI
縮寫表 XII
第一章、緒論 1
第一節、台灣石斑魚養殖概況 1
(一) 石斑魚背景介紹 1
(二) 魚苗養殖概況與瓶頸 2
第二節、神經壞死病毒簡介 3
(一) 神經壞死病毒之發現 3
(二) 神經壞死病毒之分類 4
(三) 感染神經壞死病毒之病理特徵 4
(四) 神經壞死病毒基因與蛋白質功能研究 4
(五) 神經壞死病毒與細胞死亡之研究 5
第三節、自噬作用 7
(一) 自噬作用的發現與型式 7
(二) 自噬作用的機制與調控 8
第四節、自噬作用與病毒感染之互動 9
(一) 病毒引起自噬作用 10
(二) 自噬作用影響病毒增值 10
第五節、Bcl-2家族蛋白 11
(一) Bcl-2家族蛋白分類與特性 11
(二) Bcl-2家族蛋白與細胞凋亡 12
(三) Bcl-2家族蛋白與自噬作用 13
第六節、氧化壓力與細胞死亡 14
(一) 活性氧分子(ROS)的產生和來源 14
(二) 活性氧分子與氧化壓力(oxidative stress) 15
(三) 抗氧化系統 16
(四) Bcl-2家族蛋白與氧化壓力的調控 16
第七節、研究目的與動機 18
第二章、材料與方法 19
第一節、實驗材料 19
(一) 生物材料 19
(二) 抗體 19
(三) 細胞用試藥 20
(四) 生物反應試劑組(Kits) 21
(五) 載體 21
(六) siRNA序列 21
(七) 細菌培養基與抗生素之配製 22
(八) 細胞培養液試藥 22
(九) 細胞培養液配製 22
(十) 蛋白質樣本萃取溶液 23
(十一) 蛋白質電泳及膠體製作緩衝溶液 24
第二節、實驗儀器 27
第三節、實驗方法及步驟 29
(一) 菌種的培養及菌種的儲存 29
(二) 萃取質體DNA 29
(三) 聚合酵素連鎖反應 (PCR) 30
(四) 膠體萃取 30
(五) 質體剪接及黏合反應 31
(六) 轉形反應(transformation) 32
(七) 細胞培養 32
(八) 病毒增殖與效價測定 34
(九) 蛋白質表現測定 35
(十) MTT細胞存活率測定 36
(十一) Annexin V/Propidium iodide染色分析細胞死亡 37
(十二) 粒線體膜電位測定 37
(十三) 細胞內ROS含量變化之測定 37
(十四) 細胞內自噬體形成之測定 39
(十六) siRNA knockdown 39
第三章、結果 41
第一節、神經壞死病毒誘發ATG5參予自噬作用並促進病毒複製 41
第二節、在石斑魚背鰭細胞株中大量表現Bcl-2家族蛋白Bcl-2或Bcl-xL可抑制神經壞死病毒誘發的細胞死亡 42
(一) 利用PI染色偵測細胞存活率 42
(二) 使用PI/Annexin V染色偵測細胞死亡形態 43
(三) 大量表現Bcl-2或Bcl-xL可降低病毒感染後necrotic death相關基因RIP3的表現 44
第三節、大量表現Bcl-2或Bcl-xL可抑制神經壞死病毒誘發自噬作用並減少病毒複製 45
(一) 大量表現Bcl-2或Bcl-xL可降低病毒感染誘導的自噬作用發生 45
(二) 大量表現Bcl-2或Bcl-xL可減緩病毒複製與增殖 46
第四節、大量表現Bcl-2或Bcl-xL可抑制病毒造成的粒線體損傷 47
(一) 大量表現Bcl-2或Bcl-xL可減緩病毒誘發的粒線體膜電位喪失 47
第五節、大量表現Bcl-2或Bcl-xL可減少病毒感染所產生的ROS 48
(一) 使用Carboxy-H2DCFDA染劑偵測病毒感染後大量表現Bcl-2或Bcl-xL對細胞內ROS含量的影響 49
(二) 利用MitoSOX Red染劑偵測病毒感染後大量表現Bcl-2或Bcl-xL對細胞內O2-含量的變化 49
(三) 利用Amplex Red染劑偵測病毒感染後大量表現Bcl-2或Bcl-xL對細胞內H2O2含量的變化 50
第六節、大量表現Bcl-2或Bcl-xL會增加抗氧化酵素表現 51
第七節、大量表現Bcl-2或Bcl-xL可減緩tBHQ產生ROS 51
(一) 大量表現Bcl-2或Bcl-xL可減少ROS促進劑tBHQ造成的細胞死亡 52
(二) 大量表現Bcl-2或Bcl-xL可減少ROS促進劑tBHQ處理後產生的O2-與H2O2 52
第八節、以BH3 domain結構類似物ABT-199抑制Bcl-2活性後會喪失調節細胞死亡與ROS的能力 53
(一) 大量表現Bcl-2細胞株中添加ABT-199會增加病毒感染後的細胞死亡率 54
(二) 大量表現Bcl-2細胞株中添加ABT-199會增加病毒誘發的粒線體膜電位喪失 54
(三) 大量表現Bcl-2細胞株中添加ABT-199會增加受感染細胞內superoxide的產生 55
(四) 大量表現Bcl-2細胞株中添加ABT-199會增加病毒所誘發的自噬作用 56
第四章、討論 57
第一節、自噬作用與神經化死病毒複製關係 57
第二節、Bcl-2、Bcl-xL如何調節病毒誘發的細胞死亡 59
第三節、Bcl-2、Bcl-xL如何調節病毒誘發的自噬作用 60
第五章、未來展望 63
參考文獻 64


圖表目錄
表一. 病毒效價TCID50 之測定(Reed-Muench 公式) ................................75
表二、引子設計.............................................................................................76
圖一、利用siRNA方式抑制ATG5表現可增加細胞對RGNNV的抗性........................................................................................................77
圖二、利用siRNA抑制ATG5可減少神經壞死病毒所引起的自噬作用........................................................................................................78
圖三、利用siATG5抑制自噬作用可減少病毒蛋白表現量......................79
圖四、大量表現Bcl-2與Bcl-xL細胞株之表現情形................................80
圖五、大量表現Bcl-2或Bcl-xL可減少病毒誘發的細胞壞死現象........81
圖六、大量表現Bcl-2或Bcl-xL可減少病毒誘發的細胞凋亡與壞死現象........................................................................................................83
圖七、大量表現Bcl-2或Bcl-xL可減少病毒感染所誘發的細胞凋亡與壞死比例之改變....................................................................................85
圖八、大量表現Bcl-2或Bcl-xL抑制病毒感染所誘發的細胞壞死相關蛋白表現................................................................................................87
圖九、大量表現Bcl-2或Bcl-xL可減少神經壞死病毒誘發的自噬體形成........................................................................................................88
圖十、大量表現Bcl-2可減少神經壞死病毒所引起的自噬作用..............90
圖十一、大量表現Bcl-xL可減少神經壞死病毒所引起的自噬作用........91
圖十二、大量表現Bcl-2可減少病毒蛋白表現與病毒效價......................92
圖十三、大量表現Bcl-xL可減少病毒蛋白表現與病毒效價....................93
圖十四、大量表現Bcl-2或Bcl-xL可減少病毒誘發的粒線體膜電位喪失現象................................................................................................94
圖十五、大量表現Bcl-2或Bcl-xL可減少受感染細胞內H2O2含量的增加....................................................................................................96
圖十六、大量表現Bcl-2或Bcl-xL可減少受感染細胞內superoxide的產生....................................................................................................98
圖十七、病毒感染大量表現Bcl-2或Bcl-xL細胞株後對細胞內抗氧化酵素表現量之影響...........................................................................100
圖十八、大量表現Bcl-2或Bcl-xL細胞株可抑制tBHQ誘發的細胞死亡...................................................................................................102
圖十九、大量表現Bcl-2或Bcl-xL細胞株可抑制處理tBHQ後產生的ROS...............................................................................................103
圖二十、添加Bcl-2抑制劑ABT-199會增加病毒感染後的細胞死亡率...................................................................................................105
圖二十一、添加Bcl-2抑制劑ABT-199會增加病毒誘發的粒線體膜電位喪失現象.......................................................................................106
圖二十二、Bcl-2抑制劑ABT-199會增加受感染細胞內superoxide的產生...................................................................................................108
圖二十三、Bcl-2抑制劑ABT-199會增加病毒感染所誘導的自噬作用...................................................................................................110
圖二十四、Bcl-2或Bcl-xL在病毒感染時可能扮演的角色....................111

附錄目錄
附錄一、石斑魚神經壞死病毒基因組結構圖...........................................112
附錄二、三種不同類型的自體吞噬作用...................................................113
附錄三、自體吞噬作用的調節機制...........................................................114
附錄四、Bcl-2家族蛋白所參予的細胞死亡與自噬作用途徑.................115
附錄五、pEGFP-N3-zfBcl-2與pEGFP-N3-zfBcl-xL質體圖譜...............116
附錄六、p3XFLAG-Myc-CMV-zfBcl-2與p3XFLAG-Myc-CMV-zfBcl-xL質體圖譜.......................................................................................117
附錄七、利用JC-1 dye偵測粒線體膜電位變化的原理...........................118
附錄八、利用Carboxy-H2DCFDA染劑偵測細胞內H2O2的原理..............119
附錄九、利用Amplex® Red偵測細胞內H2O2含量的原理.....................120
附錄十、利用MitoSOXTM Red偵測細胞內粒線體O2-的原理................121
附錄十一、由GF-1細胞株所clone出的ATG5片段基因序列與針對ATG5基因所設計出的siRNA序列........................................122
附錄十二、斑馬魚的zfBcl-2 mRNA序列................................................123
附錄十三、斑馬魚的zfBcl-xL mRNA序列..............................................124
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