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系統識別號 U0026-0703201414002100
論文名稱(中文) 血纖維蛋白溶酶原經由與凝血酶調節素結合調控傷口癒合及血管新生
論文名稱(英文) Plasminogen mediates angiogenesis and wound healing by interaction with thrombomodulin
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 102
學期 2
出版年 103
研究生(中文) 陳柏谷
研究生(英文) Po-Ku Chen
學號 s58971439
學位類別 博士
語文別 英文
論文頁數 93頁
口試委員 指導教授-吳華林
口試委員-施桂月
口試委員-賴明德
召集委員-張權發
口試委員-林淑華
口試委員-王寧
中文關鍵字 血管新生  傷口癒合  凝血酶調節素  血纖維蛋白溶酶原 
英文關鍵字 wound healing  angiogenesis  thrombomodulin  plasminogen  diabetic wound 
學科別分類
中文摘要 血纖維蛋白溶酶原 (plasminogen, Plg) 活化系統包含Plg/血纖維蛋白溶酶(plasmin, Plm),尿激酶型血纖維蛋白溶解酶原活化因子(urokinase-type plasminogen activator, uPA)與其接受器(urokinase-type plasminogen activator receptor, uPAR),主要參與細胞周圍蛋白水解功能進而調控血管新生(angiogenesis)與傷口癒合(wound healing)。然而,在細胞移行過程中, Plg接受器經由uPA促進Plg活化的機制仍有待被探討。在第一部份的研究中,我發現一個新的Plg接受器即穿膜醣蛋白凝血酶調節素(thrombomodulin,TM),此蛋白在細胞周圍的蛋白水解及細胞移行皆扮演重要角色。我發現細胞表面Plg的活化以及Plg促進細胞移行及入侵能力都與細胞膜的TM表現量呈正相關。經由表面電漿共振(SPR)分析,發現TM胞外功能區可直接與Plg結合,其解離常數約0.1到0.3 μM。另外,於正在移行的內皮細胞前緣可觀察到TM、Plg及uPAR三者共同存在脂筏微區塊 (lipid raft microdomain),且與細胞周圍蛋白水解區域重疊。經由皮膚傷口癒合模式證明,TM與Plg在血管新生過程扮演重要角色。在第二部份的研究中,我探討在傷口癒合中所形成Plg/TM/uPAR複合體及其功能。在傷口初期,可觀察Plg/TM/uPAR複合體的形成並且誘導Plm的產生;反之,在TM上皮細胞缺失的老鼠中,Plm的產生則明顯減少。Plg可誘導生長因子產生並且增加細胞移行與生長;此現象與TM表現呈正相關。高血糖造成皮膚細胞TM表現量顯著減少,導致細胞移行與生長能力降低。此外,在上皮細胞TM缺失時,Plg所誘導的生長因子之釋放則顯著地減少。總合以上結果,TM/Plg 與uPA/uPAR結合所形成的複合體可能在細胞移行過程中,調控細胞周圍蛋白水解活性上扮演重要角色。更進一步發現,Plg/TM/uPAR複合體促進上皮細胞生長與移行是經由增加生長因子的釋放。本論文的發現,對於Plg活化所參與生長因子釋放的機制,在急性及慢性的傷口治療應用上提供一個新的方向。
英文摘要 The plasminogen activation system, including plasminogen (Plg)/plasmin (Plm), urokinase-type plasminogen activator (uPA), and urokinase-type plasminogen activator receptor (uPAR), mainly controls pericellular proteolysis in angiogenesis and skin wound healing. However, the Plg receptor that participates in uPA-mediated Plg activation has not yet been identified. In the first part of this study,Idemonstrated that thrombomodulin (TM), a type I transmembrane glycoprotein, is a novel Plg receptor that plays a role in pericellular proteolysis and cell migration. Plg activation at cell surface, and the extent of its cell migration- and invasion-promoting effect, are cellular TM expression dependent. Direct binding of Plg and recombinant TM extracellular domain, with a KD of 0.1 to 0.3 μM, was determined through surface plasmon resonance analysis. Colocalization of TM, Plg, and uPA receptor within plasma membrane lipid rafts, at the leading edge of migrating endothelial cells, was demonstrated, and was also shown to overlap with areas of major pericellular proteolysis. Moreover, the roles of TM and Plg in neo-angiogenesis were demonstrated in vivo through the skin wound-healing model. In the second part of this study, I investigated the role of Plg/TM/uPAR complex in skin wound healing. This complex was formed during early period of injured wound where the Plm production was promoted. On the other hand, the Plm production was decreased in wound healing of epidermal TM-knockout mice. Plg could induce growth factors expression to increase cell migration and proliferation in a TM-dependent manner. TM expression in keratinocytes was significantly down-regulated in hyperglycemic conditions, resulting in decrease of cell migration and proliferation. In addition, Plg-induced growth factors expression were diminished in TM knockdown keratinocytes. In conclusion, TM/Plg in conjunction with uPA/uPAR complex may play a critical role in regulation of pericellular proteolytic activity during cell migration; furthermore, this complex is responsible for the increase of growth factor expression that promotes keratinocyte migration and proliferation. These findings provide a novel insight into Plg activation in regulating growth factors expression that may have therapeutic applications to treat acute or chronic wound.
論文目次 中文摘要 I
ABSTRACT II
誌謝 IV
CONTENTS VI
FIGURE CONTENTS IX
LIST OF ABBREVIATIONS X
1. INTRODUCTION 1
1.1 Wound healing 1
1.2 Angiogenesis 2
1.3 Cell migration 3
1.4 Plasminogen 3
1.5 The role of Plg receptor in cellular functions 6
1.6 Thrombomodulin (TM) 8
1.7 The role of TM in skin wound healing and in vascular endothelium 9
1.8 Objectives of the study 10
2. MATERIAL AND METHODS 12
2.1 Reagents 12
2.2 Mouse excisional skin wound model 13
2.3 Cells and cell culture 14
2.4 Short hairpin RNA 15
2.5 Cell migration and invasion assay 15
2.6 Plg activation catalyzed by uPA on cell surface 16
2.7 Thrombin bound to coated rTMD123 16
2.8 ELISA 17
2.9 Flow cytometry 17
2.10 Immunoprecipitation and immunoblot analysis 18
2.11 Surface plasmon resonance (SPR) analysis 18
2.12 Growth factor secretion 19
2.13 Proliferation assay 19
2.14 Scratch wound migration 19
2.15 Immunofluorescence microscopy 19
2.16 Isolation of LR microdomains 20
2.17 Zymography 21
2.18 Statistical analysis 21
3. RESULTS 23
Results_Part I 23
3.1 Effect of TM expression on Plg-enhanced cell migration and invasion 23
3.2 Effect of TM expression on Plg-induced angiogenesis in mouse excision wound model 23
3.3 Efect of TM expression on uPA-mediated cell surface Plg activation 24
3.4 Binding of Plg to TM at endothelial cell surface 25
3.5 Determining the binding affinity of Plg and TM domains 25
3.6 Plg, TM, and uPAR localization to lamellipodia in migrating HUVECs 26
3.7 Distribution of TM/Plg and uPAR in LRs 27
Results_Part II 28
3.8 The expression and the association of Plg, TM, and uPAR in mouse model of excisional skin wounds. 28
3.9 TM on keratinocyte facilitates Plm generation in vitro and cutaneous wound healing in vivo. 29
3.10 TM is important for Plg/Plm-increased HaCaT cell proliferation and cell migration. 29
3.11 TM facilitates Plg-induced expression of VEGF and FGF-2 in HaCaT cells. 30
3.12 High glucose down-regulates TM expression in vitro and in vivo. 31
3.13 Down-regulation of epithelial TM in high glucose condition diminishes Plg-induced expression of VEGF and FGF-2. 32
4. DISCUSSION 33
4.1 Discussion_ Part I 33
4.2 Discussion_ Part II 37
5. CONCLUSION 42
REFERENCES 44
FIGURES 59
Table 90
Appendix 91
PUBLICATION 93
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