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系統識別號 U0026-1308201412385400
論文名稱(中文) 半乳糖凝集素-1在纖維母細胞活化以及傷口癒合中扮演之角色
論文名稱(英文) The Role of Galectin-1 in Myofibroblast Activation and Wound Healing
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) 林岳德
研究生(英文) Yueh-Te Lin
學號 S58981345
學位類別 博士
語文別 英文
論文頁數 103頁
口試委員 指導教授-陳玉玲
召集委員-林秋烽
口試委員-洪澤民
口試委員-吳梨華
口試委員-陳惠文
口試委員-陳健尉
中文關鍵字 半乳糖凝集素-1  纖維母細胞  傷口癒合 
英文關鍵字 galectin-1  fibroblast  wound healing 
學科別分類
中文摘要 真皮纖維細胞/肌成纖維細胞在傷口癒合中扮演重要的角色,並且可以藉由分泌生長因子以及化學引誘物,替傷口製造細胞外基質所需要的蛋白質並重新促使組織癒合。在傷口癒合的過程中,纖維細胞活化是關鍵的步驟。Glalectin-1 是一種β-半乳糖結合凝集素 (lectin),過去文獻指出半乳糖凝集素-1參與許多生理功能,包含細胞凋亡、細胞增生、細胞侵犯以及細胞轉移。我們先前也發現在人類牙齦細胞中表現大量的半乳糖凝集素-1會促進α -平滑肌肌動蛋白表現上升。但是半乳糖凝集素-1 促進纖維細胞活化的機制尚未釐清。在本研究中,首先我們先確認半乳糖凝集素-1是否在纖維細胞活化中扮演必要的角色,並且也能夠明顯地促進細胞移動以及增生。先前文獻指出纖維細胞活化過程中,活化性氧化物產生是重要的步驟。我們發現半乳糖凝集素-1也會促進活化性氧化物的產生,其機制是藉由正相關地影響磷酸化、總量Smad3以及NADPH氧化酶 4的表現。除此之外,我們也發現半乳糖凝集素-1活化纖維細胞是藉由與神經纖毛蛋白-1的結合來活化下游蛋白的表現。在動物皮膚傷口也發現,半乳糖凝集素-1 的確也是藉由活化磷酸化、總量Smad3以及NADPH氧化酶 4的表現來促進傷口癒合。半乳糖凝集素-1除了可以加速正常傷口癒合之外,也可以促進由鏈尿佐菌素引起的糖尿病老鼠模組的傷口癒合。基於此實驗結果,半乳糖凝集素-1在未來可能是個相當具有潛力的臨床用藥蛋白。尤其是在病理上或許可以帶給病人有個良好的治癒效果。
英文摘要 Dermal fibroblasts/myofibroblasts involves in the wound healing and secretes growth factors and chemoattractants to create new substrates and proteins in the extracellular matrix (ECM). Activation of fibroblasts plays a key role in the wound healing and injury repair. Galectin-1(Gal-1) is a β - galactose - binding lectins and involves in many physiological functions, such as apoptosis, proliferation, invasion and metastasis. We have indicated that Gal-1 induced up-regulation of α-SMA, a marker of myofibroblasts, in human gingival fibroblasts (HGFs). However, the mechanism of Gal-1 induced myofibroblast activation was still unclear. In vitro study, we found that Gal-1 played an inducer in myofibroblast activation, migration and proliferation by triggering cellular reactive oxygen species (ROS) production. NADPH oxidase 4 (NOX4, a ROS producing protein) was up-regulated in Gal-1-induced myofibroblast activation. Similar to TGF-β1-induced myofibroblast activation, Gal-1 stimulated phosphorylation of Smad3 which was the upstream of NOX4. Moreover, Gal-1 induced Smad3/NOX4 pathway though Neuropilin-1/TGFBR1 in myofibroblast activation. In vivo study, Gal-1 also turned on the Smad3/NOX4 pathway during dermal myofibroblast activation and dermal wound healing. To be a clinical approach in the future, we made several cutaneous wounds per mouse and subcutaneously injected purified Gal-1 on the wound areas as animal experiments. As expected, Gal-1 accelerated general and pathological (STZ-induced diabetes mellitus) wounds healing. Taken together, Gal-1 may be a potential therapeutic target in pathological or imperfect wound healing.
論文目次 摘要 I
Abstract II
Acknowledgement III
Abbreviation V
Contents VII
Table contents IX
Figure contents X
Chapter 1. Introduction 1
1. Wound healing. 1
2. Myofibroblast Activation 2
3. ROS production is important during myofibroblast activation 4
4. ROS production and wound healing 5
5. The biological role of Gal-1 6
6. The physiological role of Gal-1 7
7. The receptors of Gal-1 in different cell types 9
8. Gal-1 and diabetes 9
9. Streptozocin induced diabetes mellitus in animal models 10
Objectives of study 11
Chapter 2. Materials and Methods 15
Chapter 3. Results 21
1. Lgals1-/- mice had delayed wound healing in cutaneous compared with wild type mice 21
2. Gal-1 played an important role in myofibroblast activation. 22
3. Gal-1 induced reactive oxygen species production in myofibroblasts 23
4. Gal-1 induced ROS generation in myofibroblasts by regulating NOX4 24
5. Gal-1 induced myofibroblast activation through Smad3/NOX4 pathway 25
6. Neuropilin-1 may be a novel receptor of Gal-1 in fibroblasts 27
7. Gal-1 regulated wound healing by Smad3/NOX4 pathway in animal models. 28
8. Gal-1 improved wound healing in animal models 29
9. Gal-1 accelerated wound healing in STZ-induced diabetes mellitus animal models 29
Chapter 4. Discussion 31
Chapter 5. Conclusion 36
References 37
Table 52
Figure 56
Appendix 99
Equipments 102
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