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研究生:李建緯
研究生(外文):Chien-Wei Lee
論文名稱:研究第三號誘捕受體在大鼠腎小管上皮-間質轉化的作用
論文名稱(外文):The Effect of DcR3 Overexpression on Tubular EMT in Rat Renal Proximal Tubular Epithelial cells
指導教授:陳紀如
指導教授(外文):Chi-Ju Chen
學位類別:碩士
校院名稱:國立陽明大學
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:2009
畢業學年度:97
語文別:中文
論文頁數:91
中文關鍵詞:第三號誘捕受體上皮間質轉化腎臟纖維化
外文關鍵詞:DcR3EMTrenal fibrosisSlugNotch
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慢性腎臟疾病是全球性的衛生問題,花費鉅大且無法根治,而慢性腎臟病患者最終會走向腎臟纖維化及末期腎臟病變。先前的研究指出腎小管進行上皮-間質轉化是導致腎臟纖維化的最主要原因。前人發現慢性腎臟病患者的近端腎小管中發現高量的第三號誘捕受體,並且和病患的癒後惡化呈現正相關,此外在腎臟發炎時,腫瘤壞死因子-α (TNF-α) 會過度表現,進而引發人類近端腎小管的上皮細胞大量表現第三號誘捕受體。因此我們認為第三號誘捕受體可能會誘導腎小管上皮細胞進入上皮-間質轉化,進而導致腎臟纖維化的發生。為了研究第三號誘捕受體和腎小管上皮-間質轉化的相互關係,我們將大第三號誘捕受體量表現於大鼠近端腎小管細胞株 (NRK-52E) 中。我們發現第三號誘捕受體會誘導細胞進入上皮-間質轉化,使得上皮鈣黏蛋白 (E-cadherin) 表現下降並失去細胞-細胞黏著的特性;而間質標記,α-平滑肌蛋白 (α-SMA) 表現上升,此時細胞會變成細長的纖維母細胞狀,並且提升細胞移動及入侵細胞外基質的能力。為了了解第三號誘捕受體如何誘導細胞進入上皮-間質轉化,我們分析各種上皮-間質轉化的誘導因子在第三號誘捕受體穩定細胞株中的表現量,結果發現上皮-間質轉化的誘導因子,Slug大量表現在第三號誘捕受體穩定細胞株;除此之外,也觀察到β-catenin蛋白的入核以及Notch訊息傳遞路徑的活化。因此推測第三號誘捕受體可誘發更多β-catenin入核以及活化Notch訊息傳遞路徑,進而促進Slug表現及其誘導的上皮-間質轉化。我也發現第三號誘捕受體能藉由增加細胞外基質,膠原蛋白IV和纖維結合蛋白的表現,導致腎臟纖維化的現象。根據實驗結果,我認為第三號誘捕受體能誘導近端腎小管細胞進行上皮-間質轉化,增加細胞外基質的堆積導致腎臟纖維化,使得腎臟病更加惡化。有鑑於此,在未來的研究,藉由阻斷第三號誘捕受體於腎臟的表現,達到減緩或是治療腎臟病的功效是一個可能的研究方向。
Chronic kidney disease (CKD) is a worldwide public health problem with a poor outcome and high cost. Patients with CKD were detected a progressive renal functional loss, which finally leads to renal fibrosis and end-stage renal disease. Previous report indicated that tubular epithelial–mesenchymal transition (TEMT) was a critical step in renal fibrosis. Besides, ectopic DcR3 expression was observed on proximal tubule in CKD patients’ kidneys and corrected to poor prognosis of CKD. We previously found that TNF-α, which was expressed in inflammatory kidney, could induce DcR3 expression in human proximal tubular epithelial cells. Therefore, we hypothesized that DcR3 could induce tubular EMT and lead to renal fibrosis. To further evaluate the role of DcR3 in tubular EMT, we overexpressed DcR3 in NRK-52E, a rat renal proximal tubular epithelial cell line. We found that DcR3 triggered the EMT processes, including loss of E-cadherin-mediated cell-cell adhesion, activation of mesenchymal markers, α-SMA, showing acquisition of a fibroblast-like morphology, and enhancement of cell mobility and invasion. Increased expression of the transcription factor, Slug, and nucleus- translocation of Notch1 intracellular domain and β-catenin were observed in DcR3-overexpressed NRK-52E cells. This data imply that the increased expression of Slug may induce by Notch1 or β-catenin translocation and that play critical roles in DcR3-induced EMT. Furthermore, we also observed that DcR3 enhanced expression of extracellular matrix proteins, such as collagen IV and fibronectin. All data suggest DcR3 overexpression in renal proximal tubular epithelial cells could induce EMT and accumulation of extracellular matrix proteins, which may finally lead to renal fibrosis in CKD patients. In future, blocking DcR3 expression in kidney may retard CKD progress, and even DcR3 could be the drug-selection target for CKD therapy.
目次

1. 中文摘要 1
2. Abstract 2
3. 緒論 3
3.1. 第三號誘捕受體 Decoy receptor 3 (DcR3) 3
3.2. 慢性腎臟疾病 6
3.3. 腎臟纖維化 (renal fibrosis) 6
3.4. 腎小管上皮-間質轉化 (tubular epithelial -mesenchymal transition) 7
3.5. Notch訊息傳遞路徑 12
3.6. 內質網壓力 (ER stress) 14
4. 實驗目的 16
5. 實驗材料 17
5.1. 細胞株 17
5.2. 細胞培養液及抗生素 (嘌呤黴素, puromycin) 17
5.3. 磷酸生理食鹽水 (phosphate-buffered saline, PBS) 17
5.4. Trypsin-EDTA 溶液 18
5.5. 細胞轉染試劑lipofectamineTM 2000及稀釋液OPTI-MEM 18
5.6. 細菌株 18
5.7. 細菌培養液,細菌培養基及抗生素 18
5.8. DNA及質體萃取套組 19
5.9. TAE電泳緩衝液及DNA電泳洋菜凝膠 19
5.10. 酵素 19
5.11. SDS聚丙烯醯胺凝膠 (SDS-PAGE) 20
5.12. 五倍SDS聚丙烯醯胺凝膠電泳緩衝液 (5x SDS-PAGE running buffer) 20
5.13. SDS聚丙烯醯胺凝膠轉印緩衝液 (SDS-PAGE transfer buffer) 20
5.14. SDS-PAGE轉印膜用蛋白質染色試劑 (ponceau s) 20
5.15. TBST緩衝液 (Tris-buffered saline contain tween- 20 buffer) 21
5.16. 細胞溶解緩衝液 (Cells lysis buffer) 21
5.17. 細胞核溶解緩衝液 (nuclei EZ lysis buffer) 21
5.18. 抗體 21
5.19. 免疫螢光染色分析試劑 (immunofluorescence assay reagents) 22
5.20. 即時聚合酶連鎖反應套組 (real-time PCR kit) 22
5.21. 細胞基質侵襲力分析套組 (matrigel invasion assay kit) 22
5.22. 蛋白質定量套組 22
6. 實驗方法 24
6.1. 建構pIRESpuro2-DcR3質體 24
6.2. 建立第三號誘捕受體穩定細胞株 26
6.3. 蛋白質萃取及定量 (Protein Extraction and Quantization) 27
6.4. 西方墨點法 (western blotting) 28
6.5. 免疫螢光染色分析 (immunofluorescence assay, IFA) 29
6.6. RNA萃取及反轉錄 (RNA extraction and reverse transcription) 31
6.7. 聚合酶連鎖反應及即時聚合酶連鎖反應 (PCR and real-time PCR) 31
6.8. 刮傷癒合分析 (scratch wound-healing assay) 32
6.9. 細胞基質侵襲力分析 (matrigel invasion assay) 32
6.10. 生長曲線及生長速率 33
7. 實驗結果 34
7.1. 建立第三號誘捕受體穩定細胞株 34
7.2. 第三號誘捕受體導致大鼠近端腎小管上皮細胞型態改變 34
7.3. 第三號誘捕受體降低大鼠上皮標記及增加間質標記表現量 35
7.4. 第三號誘捕受體促進細胞移動及細胞基質侵襲能力上升 36
7.5. 第三號誘捕受體活化FAK訊息傳遞路徑以促進細胞移動及細胞基質侵襲能力上升 37
7.6. 第三號誘捕受體促細胞外基質堆積以加速腎臟的纖維化 38
7.7. 第三號誘捕受體藉由調控Slug表現導致上皮-間質轉化 38
7.8. 第三號誘捕受體和Notch訊息傳遞路徑 39
7.9. 第三號誘捕受體和β-catenin訊息傳遞路徑 40
8. 討論 41
8.1. 第三號誘捕受體之受器和上皮-間質轉化 41
8.2. 第三號誘捕受體和整合素相關訊息傳遞路徑 41
8.3. 第三號誘捕受體和基質金屬蛋白酶的表現 42
8.4. 第三號誘捕受體可能利用促進細胞增生及抗細胞凋亡加速腎臟纖維化 43
8.5. 內質網壓力的產生可能非第三號誘捕受體專一性 43
8.6. 第三號誘捕受體誘導上皮-間質轉化尚待釐清的問題 44
9. 結論 46
10. 本篇研究的重要性 48
11. 參考文獻 49
12. 表 65
13. 圖 72
14. 附錄 86

表次

表 一: 實驗用一級及二級抗體 65
表 二: PCR primers 66
表 三: Real-time PCR primers 67
表 四: 限制酶Sac I切割pIRESpuro2-DcR3結果預期表 68
表 五: 大鼠近端腎小管上皮細胞 (NRK-52E) 對puromycin敏感性測試 69
表 六: 第三號誘捕受體穩定細胞株細胞侵襲力分析 70
表 七: 大鼠近端腎小管上皮細胞第三號誘捕受體穩定細胞株生長速率表 71










圖次

圖 一: 建立第三號誘捕受體穩定細胞株 72
圖 二: 大鼠近端腎小管細胞及第三號誘捕受體穩定細胞株的外觀形態 73
圖 三: 第三號誘捕受體降低上皮細胞標記蛋白和增加間質標記蛋白導致誘導大鼠近端腎小管細胞進入上皮-間質轉化 74
圖 四: 第三號誘捕受體降低上皮細胞標記蛋白和增加間質標記蛋白mRNA導致上皮-間質轉化的進行 75
圖 五: 第三號誘捕受體促進大鼠近端腎小管上皮細胞的細胞移動能力 76
圖 六: 第三號誘捕受體促進大鼠近端腎小管上皮細胞其細胞基質侵襲能力 77
圖 七: 第三號誘捕受體藉由增加αv-integrin和fibronectin在大鼠近端腎小管上皮細胞的表現以促進FAK訊號的活化 79
圖 八: 第三號誘捕受體增加大鼠近端腎小管細胞分泌細胞外基質的表現以促進腎臟纖維化的發生 80
圖 九: 第三號誘捕受體促進Slug轉錄因子的表現以誘導大鼠近端腎小管細胞進入上皮-間質轉化 81
圖 十: 第三號誘捕受體可能藉由活化Notch1訊息傳遞路徑進而促進Slug的表現 83
圖 十一: 第三號誘捕受體可能藉由促進β-catenin入細胞核誘導近端大鼠腎小管細胞進入上皮-間質轉化 84
圖 十二: 第三號誘捕受體誘導近端腎小管上皮細胞進入上皮-間質轉化,導致腎臟纖維化模型 85

附錄次

附錄 一: TNF-α刺激人類近端腎小管上皮細胞表現第三號誘捕受體 86
附錄 二: 第三號誘捕受體大量表現於慢性腎臟病患的腎小管上皮細胞,並和預後惡化呈現正相關 87
附錄 三: 建構pIRESpuro2-DcR3質體 88
附錄 四: 第三號誘捕受體加速大鼠近端腎小管上皮細胞 (NRK-52E) 生長 90
附錄 五: 第三號誘捕受體表現和內質網壓力 (ER stress) 呈現正相關 91
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