系統識別號 U0026-3001201218432300
論文名稱(中文) 凝血酶調節素對血管新生的調控探討
論文名稱(英文) The Regulatory Roles of Thrombomodulin in Angiogenesis
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 100
學期 1
出版年 101
研究生(中文) 郭承翔
研究生(英文) Cheng-Hsiang Kuo
學號 s5894112
學位類別 博士
語文別 英文
論文頁數 122頁
口試委員 指導教授-施桂月
中文關鍵字 凝血酶調節素 
英文關鍵字 thrombomodulin 
中文摘要 血管新生參與在正常發育以及成熟組織恆定的許多生物反應過程,而不平衡的血管新生調控會導致病理症狀。凝血酶調節素是由五個不同的結構功能區所組成的第一型穿膜蛋白。其最為人熟知的功能是透過凝血酶活化血漿酶原蛋白C來執行血管內皮細胞抗凝血機制。除了細胞膜上有凝血酶調節素之表現外,不同的凝血酶調節素片段也在人類體液中被發現,並且與許多疾病狀態下的內皮細胞損傷有關。重組凝血酶調節素的類上皮細胞生長激素結構及富含絲胺酸/蘇胺酸結構片段蛋白(rTMD23)已被證實是細胞生長素也是血管新生素。然而,凝血酶調節素的其它結構功能區在血管新生的角色尚未被研究。在本論文的第一部分目標是找尋重組凝血酶調節素的類上皮細胞生長激素結構及富含絲胺酸/蘇胺酸結構片段蛋白的血管新生活性媒介。利用點突變的方法,我們製備了多種缺失活化血漿酶原蛋白C能力的重組凝血酶調節素的類上皮細胞生長激素結構及富含絲胺酸/蘇胺酸結構片段突變蛋白。並且證實這些突變蛋白具有與野生型重組凝血酶調節素類上皮細胞生長激素結構及富含絲胺酸/蘇胺酸結構片段蛋白一樣的血管新生能力,此結果顯示對於重組凝血酶調節素的類上皮細胞生長激素結構及富含絲胺酸/蘇胺酸結構片段蛋白促進血管新生活性不需要活化型血漿酶原蛋白C能力。更進一步,我們證實重組凝血酶調節素的類上皮細胞生長素結構及富含絲胺酸/蘇胺酸結構片段蛋白藉由第一型纖維母細胞生長因子受體及syndecan4來促進血管新生。本論文的第二部分是探討重組凝血酶調節素的類凝集素結構片段蛋白(rTMD1)抗血管新生的能力。實驗結果顯示,重組凝血酶調節素的類凝集素結構片段蛋白經由與Lewis Y抗原結合可以抑制血管新生。本研究證明凝血酶調節素具有兩種對於血管新生的相反角色-重組凝血酶調節素的類上皮細胞生長激素結構及富含絲胺酸/蘇胺酸結構片段蛋白藉由第一型纖維母細胞生長因子受體來促進血管新生;然而,重組凝血酶調節素的類凝集素結構片段蛋白經由與Lewis Y抗原結合的方式抑制血管新生。總結而言,我們證實凝血酶調節素同時具有促進血管新生及抑制血管新生的能力。因此證明凝血酶調節素是凝血系統、發炎反應和血管新生的重要轉接點。
英文摘要 Angiogenesis is involved in many biological processes during normal development and during homeostasis of adult tissues, whereas unbalanced regulation of angiogenesis leads to pathological conditions. Thrombomodulin (TM) is a membrane-tethered type-I glycoprotein that consists of 5 distinct functional domains. The well-known function of TM on endothelium is to mediate anticoagulation through thrombin-dependent activation of protein C. In addition to membrane-tethered TM, various soluble fragments of TM were detected in human body fluid and correlated with endothelial damage in several pathological conditions. The recombinant epidermal growth factor-like domain plus serine/threonine-rich domain of TM (rTMD23) has been demonstrated as a mitogen and an angiogenic factor, while the angiogenic activity of the other TM domains has not been well studied. In the first part of this study, we investigated the mediators involved in rTMD23’s angiogenic activity. By using site-directed mutagenesis, we generated several rTMD23 mutants lacking the ability to activate protein C and demonstrated that their angiogenic function is similar to wild-type rTMD23, indicating that activated protein C is not required for rTMD23’s angiogenic activity. Furthermore, we demonstrated that fibroblast growth factor receptor 1 (FGFR1)/syndecan4 system may mediate rTMD23-induced angiogenesis. In the second part of this study, we explored the role of recombinant lectin-like domain of TM (rTMD1) on antiangiogenesis. Our results showed that rTMD1 inhibited angiogenesis through interaction with Lewis Y antigen. This study showed two opposite functions of TM in angiogenesis – FGFR1 mediated rTMD23-induced angiogenesis and rTMD1 inhibited angiogenesis through interaction with Lewis Y antigen. In conclusion, we demonstrated that proangiogenic and antiangiogenic activities reside within molecule TM, thus TM functions as a crosslinking point for blood coagulation, inflammatory reaction, and angiogenesis.
論文目次 Abstract 1
Abstract in Chinese 2
Acknowledgement 3
Contents 4
Table contents 6
Figure contents 7
Appendix contents 8
Abbreviations 9

Chapter 1 Introduction 11
1-1 Angiogenesis 12
1-1.1 Sprouting angiogenesis 13
1-1.2 Endothelial adherens junctions in sprouting angiogenesis 14
1-1.3 Angiogenic promoters and inhibitors 15
1-2 Thrombomodulin (TM) 17
1-2.1 Discovery of TM 17
1-2.2 THBD gene 17
1-2.3 Structure of TM 17
1-2.4 Expression and function of TM in different cell types 19
1-2.5 Soluble TM 22
1-2.6 TM and inflammation 23
1-2.7 TM and angiogenesis 25
1-3 Objectives of study 26
1-3.1 rTMD23 26
1-3.2 rTMD1 27
Chapter 2 Materials and methods 28
2-1 Expression, purification, and characterization of recombinant TM domain (rTMD) proteins and the AAV expression system 29
2-2 Protein C activity assay 30
2-3 Cell cultures 31
2-4 Cell proliferation assay 31
2-5 Cell migration assay 32
2-6 In vitro vascular tube formation assay 32
2-7 Heparin binding assay and rTMD23-Sepharose pull down assay 33
2-8 Signal transduction assay and immunoprecipitation 34
2-9 ELISA assay 34
2-10 Labeling of rTMD1 35
2-11 Surface plasmon resonance (SPR) assay 35
2-12 Immunofluorescence and confocal microscopy 35
2-13 Corneal angiogenesis assay 36
2-14 In vivo Matrigel angiogenesis assay 37
2-15 Xenografts of Lewis lung carcinoma cells 38
2-16 Animal care 38
2-17 Statistical analysis 38
Chapter 3 FGFR1 mediates recombinant thrombomodulin domains-induced angiogenesis 39
3-1 Abstract 40
3-2 Introduction 41
3-3 Results 42
3-4 Discussion 45
Chapter 4 The recombinant lectin-like domain of thrombomodulin inhibits angiogenesis through interaction with Lewis Y antigen 49
4-1 Abstract 50
4-2 Introduction 51
4-3 Results 52
4-4 Discussion 58
Chapter 5 Discussion 62
5-1 The possible mechanism by which lectin-like domain of TM interferes with its EGF-like domain-mediated angiogenesis 63
5-2 The effect of TM on cancer 63
5-3 The role of TM in vascular endothelial tube formation 64
Chapter 6 Summary and prospect 66
References 68
Tables 82
Figures 84
Appendices 114
Curriculum vitae 121
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