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研究生:賴大林
研究生(外文):Da-Lin Lai
論文名稱:剪力對內皮細胞中轉錄因子Nrf2之調控
論文名稱(外文):Regulation of Transcription Factor Nrf2 in Endothelial Cells by Shear Stress
指導教授:謝學真
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:化學工程學研究所
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:129
中文關鍵詞:內皮細胞剪力轉錄因子
外文關鍵詞:shear stressNrf2endothelial cells
相關次數:
  • 被引用被引用:1
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Nrf2 is a nuclear factor that can initiate transcription of many antioxidant response element (ARE)-mediated genes including heme oxygenase-1 (HO-1). Nrf2 has been previously found to undergo nuclear translocation in response to shear stress, in which phosphatidylinositol 3-kinase (PI3K) is involved in this process. In this study, it was found that shear stress induced translocation of cytoplasmic Nrf2 into nucleus and increased Nrf2 and HO-1 protein expression in human umbilical vein endothelial cells (HUVECs). The mRNA level of Nrf2 was found to increase in short duration. Moreover, pretreatment of HUVECs with protein synthesis inhibitors cyclohexamide (CHX) abolished Nrf2 protein expression induced by shear stress. However, pretreatment of HUVECs with PKC inhibitor calphostin C and ERK1/2 inhibitor PD98059 had no effect on nuclear translocation of Nrf2 induced by shear stress. We speculate that shear stress increases Nrf2 protein expression in HUVECs by a transcriptional mechanism that also enhances Nrf2-mediated transcriptional activation of many ARE-mediated genes. In contrast, treatment with the proteasome inhibitor (MG132) caused an accumulation of Nrf2 in nucleus and cells. This study also found that reactive oxygen species (ROS) induced the translocation of Nrf2 into nucleus and increased HO-1 protein expression. In addition, treatment with phenolic antioxidant tert-butylhydroquinone (tBHQ) induced remarkably HO-1 protein expression as well as increased the level of Nrf2 in HUVECs. Treatment of HUVECs with CHX resulted in the loss of Nrf2 within 4 h. This effect was reversed by tBHQ, indicating that tBHQ could increase Nrf2 protein stability and prevent it from proteasomal degradation. Taken together, these data suggested that Nrf2 can be regulated and activated by different mechanisms under various stimulations, which include shear stress, ROS, and tBHQ. These regulatory mechanisms include the alteration in nuclear translocation, gene expression and protein stability of Nrf2 and it’s release from Keap1. The activation of Nrf2 may result in the expression of atheroprotective HO-1 protein.

中文摘要..................................................I
Abstract..................................................III
目錄......................................................V
圖表索引..................................................IX
縮寫及符號說明............................................XII
中英名詞對照..............................................XV

第一章 緒論
1.1 動脈粥狀硬化.....................................1
1.2 研究動機與目的...................................5

第二章 文獻回顧
2.1 血管內皮細胞與剪力...............................7
2.2 蛋白激酶C (protein kinase C, PKC)................13
2.2.1 蛋白激酶C之生理角色.....................13
2.2.2 剪力對PKC訊息傳導之影響.................16
2.3 活性氧族群 (Reactive Oxygen Species, ROS)........19
2.3.1 活性氧族群之生理意義....................19
2.3.2 活性氧族群之調控........................21
2.4 血紅素氧化酶-1 (Heme Oxygenase-1, HO-1)..........26
2.4.1 血紅素氧化酶-1的功能....................26
2.4.2 血紅素氧化酶-1的調控....................28
2.5 Nuclear factor-erythroid 2 related factor2 (Nrf2).32
2.5.1 Nrf2的功能..............................32
2.5.2 Nrf2訊息傳方面的調控....................33
2.5.3 Nrf2穩定性方面的調控控..................41
2.6 tert-Butyl-hydroquinone (tBHQ)...................45

第三章 實驗材料、儀器、原理及方法
3.1 實驗材料.........................................49
3.1.1 細胞培養及流動實驗所用材料..............49
3.1.2 實驗耗材................................50
3.1.3 西方墨點轉印法所用的材料................51
3.1.4 反轉錄聚合酶連鎖反應法(RT-PCR)所用的材料.52
3.2 實驗儀器.........................................54
3.3 實驗原理與方法..........................56
3.3.1 初級臍帶靜脈內皮細胞培養................56
3.3.2 臍帶靜脈內皮細胞繼代培養................56
3.3.3 流動室之設計............................57
3.3.4 流動實驗................................62
3.3.5 蛋白質含量測定..........................62
3.3.6 細胞內特定蛋白質含量測定: Western blot..64
3.3.7 細胞核內蛋白質的抽取....................64
3.3.8 細胞內Nrf2 mRNA含量之測定:RT-PCR.......65

第四章 實驗結果與討論
4.1 剪力對轉錄因子Nrf2調控之探討.....................69
4.1.1 剪力增加內皮細胞中Nrf2及其下游HO-1的基因表現70
4.1.2 剪力對Nrf2之調控探討....................75
4.1.3 剪力對內皮細胞內之ubiquitination的影響..82
4.2 活性氧族群對Nrf2調控及下游HO-1之探討.............84
4.2.1 活性氧族群活化Nrf2並增加HO-1之表現......84
4.2.2 活性氧族群對Nrf2之調控..................89
4.3 tBHQ對Nrf2調控及下游HO-1表現之探討......91
4.3.1 tBHQ增加Nrf2及下游基因HO-1之表現........91
4.3.2 tBHQ對Nrf2調控之探討....................94
4.4 綜合討論.........................................96

第五章 結論及未來研究方向
5.1 結論.............................................103
5.2 未來研究方向.....................................108

參考文獻...............................................110


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1. 陳月春,<行政法人推動實例─國立中正文化中心改制行政法人之簡介>,《公務人員月刊》,第93期,民93.3,頁24-31。
2. 許宗力,<國家機關的法人化--行政組織再造的另一選擇途徑>,《月旦法學雜誌》,第57期,民89.2,頁26-39。
3. 孫本初、劉坤億,<第一波推動行政法人化機關之訓練需求評估>,《人事月刊》,第38卷,第33期,民93.03,頁18-33。
4. 施能傑,<政府改造的理念與應用>,《人事月刊》,第33卷,第3期,民90,頁60-76。
5. 邱吉鶴,<英美兩國績效評估制度之比較>,《研考雙月刊》,第27卷第5期,民92,頁20-32。
6. 周志宏,<公立大學法人化的質變與隱憂>,《臺灣本土法學雜誌》,第49期,民92.08,頁2-3。
7. 林明鏘,<評「行政法人法」草案-以行政院九十二年二月草案為中心 (上)>,《人事行政》,第143期,民92.03,頁6-13。
8. 林水波,<政院組織轉型的政策分析(上)>,《公務人員月刊》,第72期,民91.6,頁18-26。
9. 李建良,<論公法人在行政組織建制上的地位與功能--以德國公法人概念與法制為借鏡>,《月旦法學雜誌》,第84期,民91.5,頁43-59。
10. 石真瑛,<政府機關公法人化員工權益問題與對策之探討>,《人事月刊》,第33卷,第1期,民90.7,頁36-44。
11. 陳志華,<法人化不是組織改革的底線>,《公務人員月刊》,第93期,民93.3,頁18-23。
12. 陳淳文 ,<論法國法上之公法人>,《月旦法學雜誌》,第84期,民91.5,頁32-42。
13. 彭錦鵬,<英國政署之組織設計與運作成效>,《歐美研究》,第30卷,第3期,民89.9,頁89-141。
14. 黃銘輝,<公法人概念之學理與實務>,《憲政時代》,第24卷,第2期,民87.2,頁72-100。
15. 路蓮婷,<行政法人制度之初探以我國「行政法人」法草案為例(上)>,《研習論壇》,第38期,民93.2,頁34-38。