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系統識別號 U0026-1009201321093400
論文名稱(中文) 前胸腺激素在四氯化碳誘導的小鼠肝纖維化之角色
論文名稱(英文) The role of prothymosin alpha in carbon tetrachloride-induced mouse liver fibrosis
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 2
出版年 102
研究生(中文) 林佩儒
研究生(英文) Pey-Ru Lin
學號 s58931340
學位類別 博士
語文別 英文
論文頁數 95頁
口試委員 指導教授-蕭璦莉
召集委員-賴明德
口試委員-吳昭良
口試委員-戴明泓
口試委員-林季千
中文關鍵字 肝纖維化  前胸腺激素  四氯化碳  smad2/3  smad7  乙醯化 
英文關鍵字 liver fibrosis  prothymosin alpha  carbon tetrachloride  smad2/3  smad7  acetylation 
學科別分類
中文摘要 肝纖維化是慢性肝臟損傷時常見的癒合反應。目前已知肝纖維化的發生與 transforming growth factor beta (TGFbeta)的訊息傳遞異常有關。過去的研究已指出,前胸腺激素 (prothymosin alpha, ProT)可調整因TGFbeta所導致的單核細胞及血管內皮細胞免疫功能異常,但是對於ProT在TGFbeta功能調控的角色與機制仍不清楚。我們於人類肝硬化的組織中發現, ProT的表現量增加;但在肝臟細胞的表現量遠較其他肝臟中其他種類的細胞少。無論是否受TGFbeta刺激,ProT轉殖鼠的胚胎纖維母細胞偵測到的磷酸化smad2/3量較野生型少。透過smad binding element (SBE)調控的基因表現活性,在小鼠胚胎纖維母細胞及人類肝臟細胞株(HepG2)中,都與ProT的表現量呈現負相關。基於此,我們運用ProT轉殖鼠重複注射四氯化碳八週的模式,探討ProT表現對肝纖維化發展的影響。注射四氯化碳後,ProT基因轉殖鼠其肝臟中累積的第一型膠原蛋白量、表現fibroblast specific protein-1的細胞數目與alpha smooth muscle actin的表現量,皆明顯較野生型小鼠少;TGFbeta路徑相關因子,則呈現磷酸化smad2/3減少及smad7表現量增加的現象。在ICR小鼠模式中,若於四氯化碳誘導後第四週開始給予表現ProT 基因的腺病毒載體,ICR小鼠肝纖維化的程度也明顯減輕。在小鼠肝臟細胞與HepG2細胞中,我們運用過度表現ProT基因或以shRNA降低細胞內ProT的方式,亦發現 smad7的表現量與 ProT呈現正相關;但是smad7 RNA的表現並未呈現相同的關聯性。ProT對於SBE調控基因表現,主要是透過 smad7對 smads訊息傳遞的抑制作用達成。在此路徑中,磷酸化smad2/3及smad4的表現皆會受到ProT表現的影響。我們進而發現,ProT可增強 acetyltransferase p300對 smad7的乙醯化,進而提升smad7的穩定性。我們也在誘導肝硬化的ProT基因轉殖鼠肝臟中,證實乙醯化smad7量增加的現象。這些研究結果證明ProT可透過增加smad7的方式減輕肝臟纖維化的程度,是未來可行的肝臟纖維化治療新方向。
英文摘要 Liver fibrosis, a common scarring response to chronic liver injury, is associated with malfunction of transforming growth factor beta(TGFbeta) signaling. Previous studies have shown that prothymosin alpha (ProT) treatment restored the TGFbeta-induced immunosuppressive responses on monocytes and endothelial cells. To date, the role of ProT in TGFbeta signaling has not been characterized. We screened human liver cirrhosis tissue microarray and found higher ProT expression in human cirrhotic tissues than in normal ones, except hepatocytes. Regardless of TGFbetainduction, mouse embryonic fibroblasts (MEF) of ProT transgenic mice showed less phosphorylated smad2/3 which is key mediators of TGFbetasignaling. ProT expression level is associated with smad binding element (SBE)-mediated gene expression in MEF and human HepG2 hepatoma cells. To better define the role of ProT, we induced liver fibrosis in ProT transgenic mice by repetitive carbon-tetrachloride (CCl4) injections for 8 weeks. ProTtransgenic mice displayed less collagen type I accumulation, fibroblast specific protein-1 expressing cells, andalphasmooth muscle actin expression than wild-type mice after being exposed to CCl4. A reduced phosphorylated smad2/3 and an increase of smad7 protein, an antagonist of TGFbeta signaling pathway, were observed in liver tissues after CCl4 administration. Overexpression or knockdown of ProT in mouse primary hepatocytes and HepG2 cells showed that smad7 protein level, but not RNA level, was correlated with ProT expression. Smad7 was the major mediator of ProT inhibitory effect on SBE-mediated transcriptional activity, which downregulated p-smad2/3 and smad4 levels. ProTenhanced acetyltransferase p300-mediated acetylation on smad7, thereby maintaining the stability of smad7.Increased acetylated smad7 was also observed in liver homogenates of CCl4 treated ProT transgenic mice. The results of adenovirus-mediated gene delivery of ProT for CCl4-induced liver fibrosis in ICR mice were coincident with ProT transgenic mice. Collectively, our results demonstrate that ProT attenuated liver fibrosis through enhancing smad7 protein, which might be a potential therapeutic approach for liver fibrosis.
論文目次 中文摘要....................................................I
Abstract..................................................II
誌 謝...................................................IV
List of Table...........................................VIII
List of Figures...........................................IX
List of Appendixes........................................XI
Introduction...............................................1
The history of ProT........................................1
Structure of ProT..........................................2
Post-translational modifications of ProT...................3
Transcriptional regulation of ProT.........................4
Positive regulation of ProT................................5
Negative regulation of ProT................................6
The biological functions of ProT...........................6
Intracellular functions....................................6
Extracellular functions of ProT............................9
ProT in cancer............................................13
Development of liver fibrosis.............................15
Diagnosis of liver fibrosis...............................15
TGFb in liver fibrosis....................................18
TGFb signaling............................................19
Negative regulation of TGFb signaling.....................22
Animal models of experimental liver fibrosis..............22
Specific aims.............................................23
Materials and Methods.....................................24
Antibody list.............................................24
Cell lines................................................25
Human liver cirrhosis and hepatitis tissue array..........25
Vectors and plasmids......................................25
Immunohistochemistry......................................26
Cell culture..............................................27
Isolation of mouse primary hepatocytes....................27
Animal model..............................................27
Hepatic ultrasound imaging................................28
Sirius red stain..........................................28
Immunoprecipitation and western blotting..................28
Reporter assay............................................29
RNA isolation and polymerase chain reaction...............29
Statistics................................................30
Results...................................................31
Increased ProT expression in bile duct epithelium and infiltrating immune cells of human liver tissue microarray................................................31
ProT expression interfered with smad2/3 and p38 MAP kinase signaling pathways in HepG2 cells.........................31
Overexpression of ProT attenuated Smad2/3-mediated TGFb responsiveness............................................32
ProT transgenic mice exhibited slight fibrotic changes after CCl4 induction......................................33
ProT transgenic mice attenuated phosphorylation of smad2/3 after CCl4 induction......................................34
ProT overexpression enhanced smad7 protein level..........34
Knockdown of smad7 expression abrogated the inhibitory effect of ProT acting on SBE-mediated gene expression.....35
Overexpression of ProT increased the stability of smad7 protein...................................................36
ProT gene therapy suppressed the progression of liver fibrosis in CCl4-induced animals..........................37
Discussion................................................38
Conclusions...............................................47
Future Perspectives.......................................48
References................................................49

List of Table
Table 1. Expression of ProT in different cell types of human liver tissues.......................................71

List of Figures
Fig. 1. Expression pattern of ProT in human cirrhotic liver tissue microarray.........................................72
Fig. 2. Effects of TGFbeta signaling pathway in ProT overexpressing/ knockdown HepG2 cells.....................73
Fig. 3. Overexpression of ProT attenuates smad2/3-mediated signaling.................................................75
Fig. 4. Expression level of ProT affects the smad-binding element mediated gene expression..........................76
Fig. 5. ProT overexpression causes no histological abnormality in the mouse liver............................77
Fig. 6. ProT transgenic mice exhibit less liver fibrotic changes than wild type ones after CCl4 induction..........78
Fig. 7. ProT transgenic mice contain less FSP-1-expressing cells in liver tissues after CCl4 induction...............80
Fig. 8. ProT transgenic mice express less alphaSMA in liver tissues after CCl4 induction..............................81
Fig. 9. ProT overexpression suppresses smad2/3-mediated TGFbeta signaling in the CCl4-induced liver fibrosis model.....................................................82
Fig. 10. ProT expression affected the expression of smad7 at protein level in HepG2 cells...........................83
Fig. 11. ProT expression affected the expression of smad7 at protein level in primary mouse hepatocytes.............84
Fig. 12. ProT expression suppressed SBE-mediated gene expression through smad7..................................85
Fig. 13. Elevation of acetylated smad7 is associated with overexpression of ProT....................................86
Fig. 14. Elevation of acetylated smad7 is associated with overexpression of ProT....................................87
Fig. 15. ProT gene delivery inhibits the progression of CCl4-induced liver fibrosis in ICR mice...................88
Fig. 16. ProT gene delivery decreases the number of FSP-1-expressing cells in CCl4-induced liver fibrosis model.....89
Fig. 17. ProT gene delivery attenuates p-smad2/3 level and enhances smad7 protein level in liver tissues of CCl4-induced liver fibrosis model..............................90

List of Appendixes
Appendix 1. Expression profiles of ProT in normal human and mouse tissues.............................................91
Appendix 2. Structure of ProT protein.....................92
Appendix 3. Schematic illustration of fibrosis progression...............................................93
Appendix 4. Schematics of TGFbeta/smads signaling.........94
Appendix 5. A proposed model of ProT in modulating TGFbeta/smads signaling...................................95
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