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系統識別號 U0026-0812200915144861
論文名稱(中文) 製造並探討重組巨噬細胞移動抑制因子及其抗體之特性
論文名稱(英文) Generation and characterization of recombinant macrophage migration inhibitory factor and its antibodies
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 97
學期 2
出版年 98
研究生(中文) 莊淵州
研究生(英文) Yuan-Chou Chuang
學號 t3696104
學位類別 碩士
語文別 中文
論文頁數 108頁
口試委員 口試委員-林克亮
口試委員-傅子芳
指導教授-葉才明
中文關鍵字 巨噬細胞移動抑制因子  單株抗體  發炎  噬菌體展示系統 
英文關鍵字 inflammation  MIF  phage display  monoclonal antibody 
學科別分類
中文摘要 巨噬細胞移動抑制因子(MIF)是一種發炎性細胞激素,並且在許多疾病中扮演重要角色,如:動脈粥狀硬化、癌症、自體免疫疾病以及感染疾病等。因此,製造重組蛋白與抗體來探討其功能及應用在疾病診斷及治療是非常有價值的。在本篇研究中,我們利用大腸桿菌表現了具有功能的重組人類MIF(rhMIF)及小鼠MIF蛋白。純化之rhMIF具有互變異構酶酵素活性,並且其活性可以藉由小分子抑制劑ISO-1來抑制。rhMIF也可以誘導人類周邊血單核球分泌腫瘤壞死因子α(TNF-α)及介白素1β(IL-1β),而此現象可由抗MIF血清或ISO-1來抑制。利用流式細胞儀也偵測到rhMIF會使人類單核球細胞株THP1表面之細胞黏附因子1(ICAM-1)表現量上升。此外,我們也發現rhMIF能刺激人類血管內皮細胞(HMEC-1)通透性增加。我們利用rhMIF免疫小鼠製造出單株抗體S1。S1除了能夠辨識rhMIF,同時也從不同樣本中分別利用西方點墨法、流式細胞儀、免疫螢光染色等方法確認此抗體也可辨識原生MIF。此外,我們也使用12-mer噬菌體胜肽展示系統來預測S1結合的抗原決定位,並且以GCG軟體分析辨識的序列。最後,我們使用S1單株抗體探討不同疾病模式中MIF的表現。總結,我們利用細菌系統表現出具有生物活性的MIF重組蛋白並製造出其株抗體,未來希望以本實驗為基礎,以動物模式探討MIF的重要性。
英文摘要 Macrophage migration inhibitory factor (MIF) is an important inflammatory cytokine that plays important roles in many different diseases such as atherosclerosis, cancer, autoimmune diseases and infection. Therefore, it is very valuable to generate recombinant MIF protein and its antibody for diagnostic development and therapeutic strategies. In this study, we successfully expressed recombinant human MIF (rhMIF) and murine MIF protein using bacterial system. The purified rhMIF had tautomerase activity which was inhibited by its inhibitor, ISO-1. rhMIF could also stimulate the secretion of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) in human peripheral blood mononuclear cells (PBMCs), which were inhibited in the presence of MIF anti-sera or ISO-1. The expression of intercellular adhesion molecule-1 (ICAM-1) in human monocytic cell line THP1 after rhMIF stimulation was also increased as shown by flow cytometry assay. Moreover, we found that rhMIF could increase the permeability of human dermal microvascular endothelial cell line (HMEC-1). Monoclonal antibody (S1) against rhMIF was generated from rhMIF immunized mice. This monoclonal antibody not only could recognize rhMIF but also recognize native human MIF as determined by different methods such as Western blot, flow cytometry assay and immunofluorescent assay using different specimens. The epitope recognized by S1 was also identified using phage-displayed random 12-mer peptide library and the consensus sequence was analyzed by GCG program. Finally, we characterized the expression of MIF in different disease model using S1. In conclusion, we generated and expressed functional recombinant MIF protein and monoclonal antibody which can be used to study the biological significant of MIF in vivo in future.
論文目次 總目錄
1. 總目錄...........................................................................................................I
2. 縮寫指引....................................................................................................VI
3. 圖表目錄..................................................................................................VII
4. 緒論.......................................................................................................1
4.1 免疫反應與細胞激素............................................................................1
4.2 MIF的歷史............................................................................................2
4.3 MIF的基因及蛋白結構與表現............................................................3
4.3.1 基因結構......................................................................................3
4.3.2 蛋白結構與表現..........................................................................4
4.4 MIF的作用及意義................................................................................4
4.4.1 MIF的訊息傳遞路徑及作用.......................................................5
4.4.2 MIF與先天性免疫反應...............................................................6
4.4.3 MIF與後天性免疫反應...............................................................7
4.4.4 MIF對疾病的影響.......................................................................8
4.4.5 MIF在臨床診斷的意義...............................................................9
5. 實驗動機與目標........................................................................................11
6. 實驗材料與方法.................................................................................12
6.1 構築及表現人類及小鼠MIF...............................................................12
6.1.1 構築人類及小鼠MIF.................................................................12
6.1.1.1RNA 萃取及反轉錄聚合酵素鏈鎖反應(RT-PCR)............12
6.1.1.2勝任細胞的製備(Competent cell).......................................15
6.1.1.3質體構築(construction)及轉形(transformation).................16
6.1.2 表現人類及小鼠MIF.................................................................18
6.1.2.1重組蛋白的表現及純化.....................................................18
6.1.2.2重組蛋白SDS-PAGE膠體電泳..........................................21
6.1.2.3重組蛋白的西方點墨法分析..............................................22
6.2 人類MIF重組蛋白的功能分析..........................................................23
6.2.1 人類MIF重組蛋白之互變異構酶活性測試............................24
6.2.2 人類MIF重組蛋白對人類週邊血液單核球細胞產生細胞激素之影響........................................................................................24
6.2.3 人類MIF重組蛋白對人類急性單核球細胞之細胞黏附因子表現的影響....................................................................................26
6.2.4 人類MIF重組蛋白對血管內皮細胞通透性之影響................27
6.3 人類MIF抗體的製作..........................................................................29
6.3.1 免疫小鼠及血清製備................................................................29
6.3.2 血清抗體效價的測定................................................................29
6.3.3 血清抗體的功能測定................................................................30
6.3.4 單株抗體的製備......................................................................30
6.4 人類MIF單株抗體S1分析.................................................................33
6.4.1 人類MIF單株抗體S1之抗體分型測定...................................33
6.4.2 利用ELISA測試人類MIF單株抗體S1之結合能力...............34
6.4.3 利用西方點墨法測試人類MIF單株抗體S1之結合能力.......34
6.4.4 測試人類MIF單株抗體S1結合至原生蛋白...........................34
6.5 預測人類MIF單株抗體S1辨識之抗原決定位.................................36
6.5.1 噬菌體效價測試........................................................................37
6.5.2 噬菌體胜肽庫之結合篩選........................................................38
6.5.3 噬菌體結合能力測試................................................................39
6.5.4 噬菌體單股DNA之萃取...........................................................39
6.5.5 模擬單株抗體辨識抗原決定位之立體結構............................40
6.6 MIF在不同疾病表現情形..................................................................40
6.6.1 MIF與高敏感C反應蛋白的關係.............................................40
6.6.2 HCV感染對MIF在細胞表現的影響.......................................40
7. 結果............................................................................................................42
7.1 構築及表現人類及小鼠MIF.............................................................42
7.1.1 構築人類及小鼠MIF.................................................................42
7.1.2 表現人類及小鼠MIF..........................................................42
7.2 人類MIF 重組蛋白的功能分析...............................................43
7.2.1 人類MIF重組蛋白之互變異構酶活性測試.............................43
7.2.2 人類MIF重組蛋白誘導人類週邊血液單核球細胞之細胞激素................................................................................................44
7.2.3 人類MIF 重組蛋白誘導人類急性單核球白血病細胞之細胞黏附因子..........................................................................44
7.2.4 人類MIF 重組蛋白促進血管內皮細胞之通透性增加...........45
7.3 人類MIF單株抗體製作.............................................................45
7.4 人類MIF 單株抗體S1 分析.....................................................46
7.4.1 人類MIF 單株抗體S1 之抗體分型測定................................46
7.4.2 利用ELISA 測試人類MIF 單株抗體S1 之結合能力...........46
7.4.3 利用西方點墨法測試人類MIF 單株抗體S1 之結合能力....47
7.4.4 測試人類MIF 單株抗體S1 結合至原生MIF 蛋白........47
7.5 預測人類MIF 單株抗體S1 之抗原決定位...........................48
7.6 MIF 在不同疾病表現情形........................................................49
8. 討論............................................................................................................50
9. 結論............................................................................................................63
10. 引用文獻....................................................................................................64
11. 圖表附錄.............................................................................................76
附錄一、MIF訊息傳遞路徑示意圖.............................................................102
附錄二、實驗耗材、試劑及抗體...................................................................103
附錄三、儀器.................................................................................................107
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