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研究生:賴又嘉
研究生(外文):Yu Chia Lai
論文名稱:G6PD缺乏的人類嗜中性球中Bcl-2蛋白量下降
論文名稱(外文):Decreased Bcl-2 protein level in human G6PD deficient neutrophils
指導教授:趙崇義趙崇義引用關係鄭美玲鄭美玲引用關係
指導教授(外文):T. Y. ChiuM. L. Cheng
學位類別:碩士
校院名稱:長庚大學
系所名稱:醫學生物技術暨檢驗學系
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:2012
畢業學年度:100
論文頁數:72
中文關鍵詞:葡萄糖六磷酸去氫酶Bcl-2
外文關鍵詞:G6PDBcl-2
相關次數:
  • 被引用被引用:0
  • 點閱點閱:139
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
葡萄糖六磷酸去氫酶Glucose-6-phosphate dehydrogenase (G6PD)是細胞內產生NADPH並維持氧化壓力平衡的重要酵素。雖然G6PD缺乏症是全世界最常見的酵素缺乏症,但我們對於G6PD缺乏會造成紅血球外其他細胞什麼影響目前所知仍然有限。先前我們實驗室曾指出在G6PD缺乏的人類包皮纖維母細胞容易因氧化壓力而導致凋亡。有趣的是,在G6PD缺乏的人類包皮纖維母細胞其Bcl-2蛋白量遠低於G6PD正常的人類包皮纖維母細胞。為了進一步探討G6PD的活性和Bcl-2蛋白量之間的相關性,我們收集了G6PD缺乏的人類嗜中性球和實驗室利用RNAi技術得到的G6PD-knockdown人類肺癌細胞A549、人類肝癌細胞HepG2以及人類血癌細胞HL-60並測其Bcl-2的量。我們發現在G6PD缺乏的人類嗜中性球中與G6PD正常的人類嗜中性球相比會有較低量的Bcl-2蛋白,可是在其他G6PD-knockdown的細胞株中則沒有明顯的差異。儘管G6PD其蛋白量與Bcl-2蛋白量之間有正相關 (R=0.96) 但其RNA卻沒有明顯的差異。而且G6PD缺乏的嗜中性球產生較多量的超氧陰離子 (superoxide, O2-.) 。此外,當受到外來的刺激時 (TNF-alpha) G6PD缺乏的嗜中性球會比較容易凋亡。總結這些數據,我們發現G6PD缺乏的嗜中性球會使得細胞內氧化壓力不平衡並導致訊息傳遞發生改變使得Bcl-2蛋白量下降。而G6PD的活性是如何影響Bcl-2蛋白量這相關的機制便是本實驗室日後的研究目標之一。
Glucose-6-phosphate dehydrogenase (G6PD) plays an important role in regulating cellular redox status by generating NADPH. Although its deficiency is the most common enzymopathy affecting over 400 million people world-wide, very little is known about how G6PD-deficiency may affect cells other than red cell. We have previously reported that human G6PD-deficient foreskin fibroblast cells (HFFs) were highly susceptible to oxidant-induced apoptosis. Interestingly, the protein level of Bcl-2 in G6PD-deficient HFFs was much lower than that in normal HFFs. To further investigate the effect of G6PD activity on Bcl-2, we correlate the relationship between G6PD status and Bcl-2 protein/RNA levels in human neutrophils as well as in several cell line with or without G6PD knockdown. Low Bcl-2 protein level was found in G6PD-deficient neutrophils. However, there was no significant change of Bcl-2 protein level in G6PD-knockdown cell lines, such as A549, HepG2 and HL-60 as compared to the control counter parts. There was no difference in RNA levels, albeit a positive correlation (R=0.96) was shown between G6PD and Bcl-2 protein in neutrophils. In response to TNF-alpha, G6PD-deficient neutrophils were more susceptible to apoptosis than normal control and such enhanced susceptibility to oxidant-induced apoptosis can be attributed to the decreased protein level of Bcl-2 in these cells. In addition, G6PD-deficient neutrophils exhibited higher level of superoxide anion than normal neutrophils. Taken together, our findings suggest that G6PD-deficient cells with increased intracellular oxidative stress and altered redox signaling are closely related to Bcl-2 protein level in human neutrophils and primary fibroblasts. The underlying mechanism of how does G6PD status affect Bcl-2 protein level is currently being investigated.
指導教授推薦書
口試委員會審定書
授權書
誌謝 iv
中文摘要 v
英文摘要 vii
目錄 ix
附錄圖表 xiii
第一章 前言 1
1.1 Glucose-6-phosphate dehydrogenase (G6PD)缺乏症與氧化壓 力 1
1.2 氧化壓力和細胞凋亡 3
1.3 Bcl-2家族蛋白 4
1.4蛋白降解作用 5
1.5 ROS和Bcl-2 6
第二章 研究目的 9
第三章 實驗流程 10
第四章 實驗材料及方法 11
4.1實驗方法 11
4.1.1收集G6PD正常與缺乏者全血並分離出嗜中性球 11
4.1.2嗜中性球蛋白質萃取與定量 12
4.1.3利用TNF-α處理人類嗜中性球 13
4.1.4細胞培養 13
4.1.5 G6PD酵素活性測試 13
4.1.6 西方墨點法 14
4.1.7 測量Caspas-3活性 15
4.1.8 測量血球細胞產生超氧陰離子之含量 15
4.1.9利用proteasome抑制劑 (Lactacystin/MG132) 處理人類嗜中性 球 16
4.1.10 全血RNA萃取及濃度測定 16
4.1.11 反轉錄聚合連酶連鎖反應 17
4.1.12 即時定量聚合酶連鎖反應 18
4.1.13 統計分析方法 18
第五章 實驗結果 19
5.1 G6PD 缺乏的人在全血及嗜中性球其G6PD活性皆明顯低於G6PD正常的人 19
5.2 G6PD 缺乏的嗜中性球其Bcl-2的蛋白量明顯低於G6PD正常嗜中性球 20
5.3 人類嗜中性球之G6PD蛋白/活性與Bcl-2蛋白量之間呈正相關 20
5.4 利用辨認不同epitope的Bcl-2抗體去確認Bcl-2蛋白在G6PD缺乏的嗜中性球蛋白量確實低於G6PD正常的嗜中性球 21
5.5 Bcl-2蛋白家族中的其他成員,在G6PD正常與缺乏的嗜中性球中沒有顯著差異 22
5.6 Bcl-2在G6PD缺乏的原代培養細胞中蛋白量會下降,在G6PD-knockdown的細胞株中則沒有這種現象發生 22
5.7 在G6PD缺乏的人類嗜中性球及G6PD–knowdown HL-60 (Neutrophil-like cell) IDH的表現量與正常組相比沒有顯著差異 23
5.8 利用TNF-α在不同時間點處理G6PD正常與缺乏的嗜中性球,發現G6PD缺乏的嗜中性球Caspase-3蛋白量與活性都比G6PD正常的嗜中性球高 23
5.9 G6PD缺乏的嗜中性球超氧陰子的產量比G6PD正常的嗜中性球高 24
5.10 在G6PD正常與缺乏的人類嗜中性球中,Bcl-2的RNA沒有差異 25
5.11 在G6PD正常與缺乏人類嗜中性球中,蛋白的ubiquitination在一般情況下沒有差異 25
5.12 利用proteasome抑制劑(Lactacystin)處理人類嗜中性球後,G6PD缺乏的嗜中性球其Bcl-2不會因proteasome抑制劑(Lactacystin)的處理而有回復的現象 26
5.13 利用proteasome抑制劑(MG132)處理人類嗜中性球後,G6PD缺乏的嗜中性球其Bcl-2不會因proteasome抑制劑 (MG132) 的處理而有回復的現象 26
第六章 討論 28
圖表 34
參考文獻 51


附錄圖表

圖 一、實驗設計流程 34
圖 二、G6PD缺乏者的G6PD活性在全血及人類嗜中性球中明顯比G6PD正常者低 36
圖 三、G6PD缺乏的人類嗜中性球中有較少量的抗凋亡蛋白Bcl-2與較高的凋亡指數(BAX/Bcl-2) 37
圖 四、人類嗜中性球之G6PD蛋白/活性與Bcl-2蛋白量之間呈正相關 39
圖 五、利用不同epitope的抗體去證實G6PD缺乏的嗜中性球的Bcl-2蛋白量確實低於G6PD正常的嗜中性球 40
圖 六、Bcl-2蛋白家族中的其他成員,在G6PD正常與缺乏的嗜中性球中沒有顯著差異 41
圖 七、G6PD缺乏的原代纖維母細胞其Bcl-2蛋白量低於正常對照,而G6PD-knockdown之A549、 HepG2以及HL-60細胞其Bcl-2量與正常對照比較並沒有明顯差異 42
圖 八、在人類嗜中性球或HL-60 (Neutrophil-like cell) 中,IDH (Isocitrate dehydrogenase)表現量沒有顯著差異 43
圖 九、凋亡相關蛋白Caspase-3的蛋白量與活性在G6PD缺乏的嗜中性球中高於G6PD正常的嗜中性球 44
圖 十、G6PD缺乏的人類嗜中性球其超氧陰離子的產量遠高於G6PD正常的人類嗜中性球 46
圖 十一、在G6PD正常與缺乏的人類嗜中性球中,Bcl-2的RNA量沒有顯著差異 47
圖 十二、在G6PD正常與缺乏人類嗜中性球中,全部蛋白的ubiquitination在正常情況下沒有差異 48
圖 十三、利用proteasome抑制劑(Lactacystin)處理人類嗜中性球後,G6PD缺乏的嗜中性球其Bcl-2不會因proteasome抑制劑(Lactacystin)的刺激而有回復的現象 49
圖 十四、利用proteasome抑制劑(MG132)在不同時間或不同濃度下處理人類嗜中性球後,G6PD缺乏的嗜中性球其Bcl-2不會因proteasome抑制劑(MG132)的處理而有回復的現象 50


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