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系統識別號 U0026-1806201016241500
論文名稱(中文) 過量表現前胸腺素誘發肺氣腫藉由抑制TGF-β 訊息傳遞路徑
論文名稱(英文) Overexpression of prothymosin α induces pulmonary emphysema by inhibition of TGF-β signalling pathway
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 98
學期 2
出版年 99
研究生(中文) 蘇秉驊
研究生(英文) Chih-Hau Su
電子信箱 s5892149@mail.ncku.edu.tw
學號 s5892149
學位類別 博士
語文別 英文
論文頁數 102頁
口試委員 指導教授-吳昭良
口試委員-賴明德
口試委員-張文粲
口試委員-蘇五洲
口試委員-吳明蒼
口試委員-戴明泓
中文關鍵字 前胸腺素  肺氣腫  乙醯化 
英文關鍵字 prothymosin  emphysema  TGF-beta  acetylation 
學科別分類
中文摘要 肺氣腫 (Emphysema)是主要的一種慢性阻塞性肺疾病 (Chronic Obstructive Pulmonary Disease, COPD) 的典型,病人的病徵是肺泡氣室的異常擴長,肺泡壁的瓦解,使得肺臟失去彈性,導致呼吸系統失去功能。根據世界衛生組織預估,慢性阻塞性肺疾病在未來20年將成為人類第4或5大死因,顯示慢性阻塞性肺疾病對人類健康的影響甚鉅。香煙是引起肺氣腫的主因,然而在抽煙族群中僅約百分之20為肺氣腫患者,顯示其中有未定義的因子涉及至此疾病。前胸線素 (Prothymosin α, 簡稱ProT) 在細胞增生、免疫調節、核醣體乙醯化調節(acetylation)、以及調控氧化壓力反應上扮演一定角色,然而前胸線素的實際生理意義仍所知有限。本篇論文主要研究前胸線素與肺氣腫的關連。我們建立前胸線素過量表現基因轉殖小鼠,發現其同型合子有肺氣腫的表現型。更重要的,我們同時在肺氣腫患者的肺組織切片中測定出前胸線素的過量表現。在前胸線素過量表現基因轉殖小鼠以及肺氣腫患者的肺樣本我們也發現抑制型Smad (I-Smad), Smad7蛋白質增加,同時受體型 Smad (R-Smad), Smad2/3, 的磷酸化下降,顯示轉型生長因子-β (Transforming growth factor-β, 簡稱TGF-β) 的訊息傳導受到抑制,而這樣的結果會造成基質金屬蛋白酵素-12 (Matrix Metalloproteinase-12,簡稱MMP-12) 的表現及活性增加,此為造成肺氣腫病徵的直接原因。更進一步,我們證明過量表現前胸線素能夠透過增加Smad7的乙醯化,加強Smad7的穩定度,進而拮抗TGF-β的訊息傳導。本篇論文的結果指出了前胸線素生理功能與肺氣腫疾病的重要性,進一步提出研究前胸線素生理功能的新方向,以及對於肺氣腫研究與應用於治療的探討。
英文摘要 Emphysema is the major type of chronic obstructive pulmonary disease (COPD), characterised by permanent airflow restriction resulting from enlargement of alveolar airspace and loss of lung elasticity. Despite being the main risk factor, only about 20% of cigarette smokers develop emphysema. Therefore, there may be unidentified genes which predispose to smoking-induced emphysema. Prothymosin α (ProT) is an acidic protein associated with cell proliferation, apoptosis, oxidative stress, immunomodulation and acetylation. Despite its many effects, the exact physiologic role of ProT remains poorly understood. Here we investigated the relevance of ProT in emphysema. We showed that overexpression of ProT leads to pulmonary emphysema in transgenic mice. Importantly, we also detected ProT overexpression in the lung epithelium from patients with emphysema. In the emphysematous lung epithelium from human and mouse samples, phosphorylated Smad2/3 levels were reduced and levels of the inhibitory Smad, Smad7, were increased, resulting in downregulation of TGF-β signalling and, in turn, increases in the production of MMP-12 and MMP-2, which are known to be associated with emphysema. Moreover, overexpression of ProT increases the acetylation, stability and activity of Smad7, which can antagonize TGF-β signalling. We have uncovered a pathway in which acetylation mediated by ProT overexpression causes emphysema through activation of Smad7. Moreover, our results implicate the possible relevance of ProT to emphysema and reinforce the importance of TGF-β signalling in the pathogenesis of emphysema.
論文目次 I. Introduction …………………………………………………………………….1
I.1. Prothymosin α (ProT)………………………………………………………..1
I.1.1 Structure of Prothymosin α…………………………………………..1
I.1.2 Biological roles of prothymosin α……………………………………2
I.1.2.1 Immunological modulation………………………………...2
I.1.2.2 Cell proliferation……………………………………………4
I.1.2.3 Anti-apoptosis………………………………………………..5
I.1.2.4 ProT and cancer…………………………………………….7
I.1.2.5 Regulation of Jak/Stat3 signal transduction……………...8
I.1.2.6. Regulation of acetylation…………………………………..9
I.1.2.7 Regulation of oxidative stress…………………………….10
I.1.3 ProTα transgenic mice……………………………………………...11
I.2. Emphysema…………………………………………………………………12
I.2.1 Emphysema is a major subtype of chronic obstructive pulmonary disease (COPD)…………………………………………………...…12
I.2.2 Inflammatory response in COPD…………………………………..13
I.2.2.1 Inflammatory cells……………………………………….13
I.2.2.2 Inflammatory mediators………………………………...14
I.2.2.3 Inflammatory regulation: the activity of histone deacetylases (HDACs) in COPD…………………………15
I.2.3 Extracellular matrix protease and anti-protease imbalance attribute to emphysema, one of the major anatomic causes of COPD………………………………………………………………..16
I.2.3.1 Neutrophil elastase has been identified the key factor for emphysema initially………………………………………16
I.2.3.2 Matrix metalloproteinases significantly involved in emphysema………………………………………………...17
I.2.3.3 Low level of antiproteases expressing in emphysema…..17
I.2.4 Oxidative stress and COPD………………………………………...18
I.2.5 Therapeutic strategies for COPD…………………………………..18
I.3. Animals models with emphysema phenotype: genetically mutant mice, transgenic mice, and induced animal model, for studying the molecular mechanisms………………………………………………………………..19
I.3.1 Gene-targeted mutant mice with emphysema phenotype………...20
I.3.2 Transgenic mice with emphysema phenotype……………………..20
I.3.2.1 Genetic mutation of ECM componets……………………20
I.3.2.2 Genetic mutant of regulators for TGF-β activation…….21
I.3.2.3 Genetic mutant involved in TGF-β signal transduction..21
I.3.2.4 Inflammatory mediator oxerexpression spontaneous induce emphysema………………………………………..22
I.3.2.5 Inflammatory mediator and protease deficient mice restrict the cigarette induced emphysema………………22
I.3.2.6 Anti-protease deficient mice have spontaneous emphysema………………………………………………..23
I.3.2.7 Antioxidant genes deficient mice are susceptible for cigarette smoke induced emphysema……………………23

II. Rationale and specific aim………………………………………………...25
II.1 Specific aim 1. To define the correlation of ProT in clinical emphysema ……………………………………………………….…….25
II.2 Specific aim 2. To study the correlation of ProT and the expression of proteases…………………………………………………………………25
II.3 Specific aim 3. To study the significance of ProT in the tissue repair signal transduction regulation………………………………………….25
II.4 Specific aim 4. To study how ProT regulate TGF-β signaling pathway………………………………………………………………….26
II.5 Specific aim 5. To study the mechanisms of the acetyl-regulated function of ProT, focusing on the inflammatory regulation………….26
II.6 Significance……………………………………………………………….27

III. Experimental design, materials and methods……………………..29
III.1 Experimental design………………………………….…………………29
III.2 Materials………………………………………………………………....31
III.2.1 Clinical samples and mice…………………….…………………..31
III.2.2 Lentiviral vectors………………………………………………….32
III.2.3 Plasmids……………………………………………………………32
III.3 Methods………………………………………………………………….34
III.3.1 Immunohistochemistry…………………………………………...34
III.3.2 Immunoprecipitation and immunoblotting……………………...35
III.3.3 Immunofluorescence……………………………………………………..36
III.3.4 RT-PCR and real-time quantitative RT-PCR analysis………….36
III.3.5 Luciferase reporter assay…………………………………………37
III.3.6 Lentivirus-mediated gene delivery……………………………….37
III.3.7 Zymography……………………………………………………….38
III.3.8 Statistical analysis………………………………………................39
IV. Results………………………………………………………………………....40
IV.1 ProT is overexpressed in the lung epithelium of patients with emphysema, and transgenic overexpression of ProT in mice leads to emphysema-like phenotype…………………………………………….40
IV.2 Overexpression of ProT upregulates the production of MMP-2 and MMP-12…………………………………………………………………41
IV.3 Overexpression of ProT downregulates TGF-β-Smad signal transduction……………………………………………………………..42
IV.4 Smad7 is accumulated in the lung epithelium in patients with emphysema and ProT transgenic mice, and ProT enhances MMP-12 expression through the upregulation of Smad7 accumulation………43
IV.5 Overexpression of ProT increases the acetylation, stability and activity of Smad7…………………………………………………………………44
IV.6 Overexpression of ProT increases the acetylation, phosphorylation, and nuclear translocation of NF-κB…………………………………...45
IV.7 Overexpression of ProT increases the acetylation, phosphorylation, and nuclear translocation of Stat3……………………………………..46

V. Discussion………………………………………………………………………48
V.1 Prothymosin α may be one of a susceptible genes for emphysema……48
V.2 The mechanism of acetyl-regulated function of ProT………………….48
V.3 ProT blockade the intracellular TGF-β signal transduction via Smad7 may be a new direction for researches of emphysema………………….49
V.4 NF-κB and Stat3 may regulate MMPs expression through ProT……..51
V.5 ProT may involve in corticosteroid resistance………………………….51
V.6 Other novel mechanisms may induce ovexpression of ProT in emphysema………………………………………………………………..52
V.7 Mechanisms of ProT in emphysema may be correlated with other diseases……………………………………………………………………53
V.7.1 ProT transgenic mice with emphysema and polycystic kidney disease……………………………………………………………….53
V.7.2 Overexpression of ProT has preliminary inhibit effect for CCl4 induced liver cirrhosis……………………………………………...54
V.8 Conclusion………………………………………………………………...55

VI. References……………………………………………………………………56
VII. Tables………………………………………………………………………...67
VIII. Figures and legends……………………………………………………...69

Figure 1. Overexpression of ProT is associated with emphysema in clinical samples. …………………………………………………………..……….69
Figure 2. ProT is overexpressed in the lung epithelium of patients with emphysema. ………....................................................................................70
Figure 3. The expression level of ProT in the normal parts of lung epithelium. 71
Figure 4. The expression level of ProT in the lung epithelium of 7 patients with mild emphysema. ………………………………………………………...72
Figure 5. The expression level of ProT in the lung epithelium of 5 patients with moderate emphysema. …………………………….……………………..73
Figure 6. The expression level of ProT in the lung epithelium of 8 patients with severe emphysema. ………………………………………………………74
Figure 7. Overexpression of ProT is associated with emphysema in transgenic mice. ………………………………………………………………………75
Figure 8. Transgenic overexpression of ProT in mice leads to emphysema-like phenotype. ………………………………………………………………..76
Figure 9. Overexpression of ProT upregulates the production of MMP-2 and MMP-12. ………………………………………………………….………77
Figure 10. Overexpression of ProT upregulates the protein production of MMP-2 and MP-12. ……………………………………………………………..78
Figure 11. Positive correlation between the mRNA levels of ProT and MMP-2 as well as ProT and MMP-12 in the lung tissue from smokers. ……….79
Figure 12. Overexpression of ProT downregulates TGF-β-Smad signal transduction in lung tissues of ProT transgenic mice and emphysema patient. …………………………………………………………………80
Figure 13. Overexpression of ProT downregulates TGF-β-Smad signal transduction in mouse embryonic fibroblasts of ProT transgenic mice. ……………………………………………………………………81
Figure 14. Reporter assay for determining Smad2/Smad3 transactivation activity. …………………………………………………………………82
Figure 15. ProT upregulates Smad3 inactivation and Smad7 protein expression. ……………………………………………………………..83
Figure 16. Smad7 is accumulated in the lung epithelium in patients with emphysema. ……………………………………………………………84
Figure 17. Smad7 is accumulated in the lung epithelium in ProT transgenic mice. ……………………………………………………………………85
Figure 18. ProT upregulates MMP-12 expression through the induction of Smad7. ………………………….………………………………………86
Figure 19. ProT overexpression enhanced MMP-12 expression is required for Smad7. ………………………………………………………………….87
Figure 20. No significant correlation between gene expression of ProT and Smad7. ………………………………………………………………….88
Figure 21. Overxpression of ProT increases the acetylation, stability and activity of Smad7 in vitro. ……………………………………………………...89
Figure 22. Overxpression of ProT increases the acetylation, stability and activity of Smad7 in vivo. ………………………………………………………90
Figure 23. Colocalization of ProT and acetylation signals in the nucleus. ….....91
Figure 24. ProT enhances p300-mediated Smad7 acetylation and stabilizes Smad7. ………………………………………………………………….92
Figure 25. ProT competitively inhibit HDAC1 binding with Smad7. …………..93
Figure 26. Smad7 acetylation in response to ProT overexpression is required for enhanced MMP-12 expression. ……………………………………….94
Figure 27. Overxpression of ProT increases the acetylation and activity of NF-κB in vitro. …………………………………………………………………95
Figure 28. Overxpression of ProT increases the acetylation of NF-κB in vivo. ..96
Figure 29. Overxpression of ProT increases the phosphorylation and nuclear localization of NF-κB. ….………………………………………………97
Figure 30. ProT upregulates the acetylation and activity of Stat3. ………….….98
Figure 31. Overxpression of ProT increases the phosphorylation and nuclear transport of Stat3. ……………………………………………………...99
Figure 32. Compare the morphology of emphysema and polycystic kidney disease of ProT transgenic mice. …………………………………….100
Figure 33. Overexpression of ProT has preliminary inhibit effect for CCl4 induced liver cirrhosis. ……………………………………………….101
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