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研究生:黃玉儒
研究生(外文):Yu-Lu Huang
論文名稱:靈芝免疫調節蛋白的作用機制及其減緩塵蟎致敏之應用
論文名稱(外文):Immunomodulatory functions of FIP-gts and prevention on Der p-sensitized mice
指導教授:柯俊良柯俊良引用關係
指導教授(外文):Jiunn-Liang Ko
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:毒理學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2003
畢業學年度:91
語文別:中文
論文頁數:120
中文關鍵詞:真菌免疫調節功能蛋白松杉靈芝PI 3-kinase干擾素-gamma塵蟎
外文關鍵詞:Fungal immunomodulatory proteinGanoderma tsugaephosphotidylinositol 3-kinaseinterferon-gammaDermatophagoides pteronyssinusFIP-gts
相關次數:
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  • 收藏至我的研究室書目清單書目收藏:2
先前由松杉靈芝(Ganoderma tsugae)當中發現的真菌類免疫調節蛋白FIP-gts (Fungal Immunomodulatory Protein),在此研究中我們利用重組蛋白工程在大腸桿菌中表現並純化得reFIP-gts。利用PI染色與流式細胞儀分析,發現FIP-gts可促使HPBMCs (Human peripheral blood mononuclear cells)的細胞週期由G0/G1期進入S期進而造成細胞增生,而預先處理PI 3-kinase (phosphatidylinositol 3-kinase)專一性抑制劑LY294002則可抑制由FIP-gts所誘導之S期的增加。另一方面分析FIP-gts誘導HPBMCs產生的細胞激素時,發現IFN-γ持續大量表現;而預先處理LY294002亦可抑制FIP-gts誘導之IFN-γ的表現;此外以Western blot方式證實,以FIP-gts處理HPBMCs後會磷酸化而活化PI 3-kinase的下游基因Akt,由此顯示PI 3-kinase在FIP-gts活化HPBMCs的過程中扮演一個相當重要的角色。另一方面,評估FIP-gts對於家塵蟎(Dermatophagoides pteronyssinus,Der p)致敏性氣喘(Allergic asthma)的減敏效果。初步發現餵食二週FIP-gts後Balb/c小鼠的脾臟細胞於體外若再以FIP-gts刺激後,反而不會誘發IFN-γ的表現;而利用白血球分類計數 (Differential Leucocyte Counting,DLC),發現致敏後Balb/c小鼠血液中之嗜鹼性球比例增加,而在餵食FIP-gts後會逐漸降低至正常範圍。然而遺憾的是我們在致敏小鼠體內無法測得血液中嗜酸性球的增加或是血清中total IgE的增加。本研究證實了FIP-gts調控HPBMCs的增生與誘導HPBMCs產生IFN-γ的機制是透過PI 3-kinase的訊息途徑;雖然在Der p致敏之動物實驗一直無法觀察到明顯誘發小鼠氣喘的病徵,但發現餵食FIP-gts後會改變Balb/c小鼠體內的免疫反應,顯示其確實具有發展成調整免疫系統之健康食品的潛能。
In this study, we expressed and purified the fungal immunomodulatory protein (FIP-gts) in E.coli. Using PI staining and flow cytometry, we found that FIP-gts promoted cell cycle progression from G0/G1 phase to S phase in HPBMCs. Pre-treatment of LY294002, a specific inhibitor of PI 3-kinase, was abolished the increased S phase induced by FIP-gts. Analyzing the cytokines induced by FIP-gts, IFN-γ persistent expressed significantly. Pre-treatment of LY294002 was also inhibited the secretion of IFN-γ stimulated by FIP-gts in HPBMCs. Moreover our results demonstrated that Akt, a downstream effecter of phosphatidylinositol 3-kinase (PI 3-kinase), was phosphorylated and activated by FIP-gts. It indicated that PI 3-kinase play an important role in the process of HPBMCs activation induced by FIP-gts. On the other part, developing allergen of house dust mite Dermatophagoides pteronyssinus (Der p)-sensitized animal model, we evaluated whether FIP-gts could attenuate the symptoms of allergic asthma. The expression of IFN-γ in the splenocytes of Balb/c mice after feeding with FIP-gts for two weeks restimulated with FIP-gts was not increased but decreased instead. Using Differential Leucocyte Counting (DLC), we found that after sensitized with Der p increased the percentage of basophils in Balb/c mice blood, after fed with FIP-gts the basophils decreased to normal level. Unfortunately, we did not observe the percentage of eosinophils and total IgE were increased in asthma Balb/c mice. Our study demonstrated that FIP-gts regulated the proliferation of HPBMCs and induced the secretion of IFN-γ in HPBMCs via PI 3-kinase activation. Though we did not observed the symptoms of allergic asthma in Der p-sensitized mice, fed with FIP-gts could truly modify the immune response in Balb/c mice. It is suggested that FIP-gts may be as a health food with immunodulatory function.
壹、中文摘要----6
貳、英文摘要----7
叁、縮寫表----9
肆、前言
一、靈芝簡介----11
二、松杉靈芝免疫調節功能蛋白 (FIP-gts)----16
三、松杉靈芝免疫調節功能蛋白具有的生理活性----17
四、體內與細胞激素相關之免疫反應----18
五、IFN-γ的相關調控機制----20
六、過敏性氣喘與衛生假說----21
七、研究動機----24
伍、實驗材料與方法
一、儀器----26
二、藥品----27
三、質體----28
四、實驗動物來源----28
五、實驗方法
1.在大腸桿菌中表現融合蛋白重組FIP-gts與純化----29
2.SDS-聚丙烯醯銨板膠電泳法----30
3.流式細胞儀分析細胞週期----32
4.細胞激素之活性測定----36
5.Western blot (西方點墨法)----40
6.塵蟎蛋白Der p的粗萃取----43
7.重組塵蟎蛋白Der pⅡ的構築與製備----43
8.塵蟎致敏動物模式的建立----50
陸、結果
一、大腸桿菌中重組FIP-gts的表現與純化----53
二、reFIP-gts免疫調節功能活性之分析─促進細胞增生----53
三、reFIP-gts免疫調節功能活性之分析─釋出細胞激素----55
四、FIP-gts刺激HPBMCs產生IFN-γ的標的細胞----56
五、探討FIP-gts誘發細胞激素之訊息傳遞途徑----58
六、本研究中二種致敏用之Der p蛋白----61
七、致敏小鼠之動物實驗----63
柒、討論----69
捌、圖目錄
圖1.pGEX4T-1-FIP-gts之構築、表現與純化----83
圖2.處理不同濃度與不同時間FIP-gts對HPBMCs細胞週期的影響----84
圖3.不同抑制劑對於FIP-gts誘導HPBMCs增生的影響----85
圖4.處理不同濃度與不同時間FIP-gts對HPBMCs誘發產生IFN-γ的影響----86
圖5.處理不同濃度與不同時間FIP-gts對HPBMCs誘發產生IL-4的影響----87
圖6.處理不同濃度與不同時間FIP-gts對T細胞之細胞週期的影響----88
圖7.不同抑制劑對於FIP-gts誘導T細胞增生的影響----89
圖8.處理不同濃度與不同時間FIP-gts對T細胞誘發產生IFN-γ的影響----90
圖9.不同抑制劑對於FIP-gts誘導HPBMCs產生IFN-γ的影響----91
圖10.處理不同濃度LY294002對於FIP-gts誘導HPBMC產生IFN-γ的影響----92
圖11.不同抑制劑對於FIP-gts誘導HPBMCs產生IL-4的影響----93
圖12.不同抑制劑對於FIP-gts誘導T細胞產生IFN-γ的影響----94
圖13.FIP-gts活化HPBMCs中Akt的情形----95
圖14.FIP-gts活化HPBMCs中GSK-3β的情形----96
圖15.FIP-gts活化HPBMCs中p38 MAPK的情形----97
圖16.FIP-gts活化HPBMCs中ERK 1/2的情形----98
圖17.FIP-gts活化HPBMCs中COX-2的情形----99
圖18.Der p誘導HPBMCs中IL-4產生的情形----100
圖19.Der p粗蛋白萃取液之製備流程說明圖----101
圖20.pGEX4T-1-Der pⅡ1-129之構築、表現與純化----102
圖21.Der p噴霧致敏用之噴霧器----103
圖22.Balb/c小鼠血液中白血球之型態----104
圖23.Der p粗蛋白致敏之Balb/c小鼠血液中的白血球分類計數----105
圖24.Der p粗蛋白致敏之Balb/c小鼠脾臟細胞於體外再次以FIP-gts刺激對於產生IFN-γ的影響----106
圖25.Der p粗蛋白致敏之Balb/c小鼠脾臟細胞於體外再次以FIP-gts刺激對於產生IL-4的影響----107
圖26.重組Der pⅡ1-129致敏之Balb/c小鼠血液中的白血球分類計數----108
圖27.重組Der pⅡ1-129致敏之Balb/c小鼠BAL液中total IgE的含量----109
圖28.餵食reFIP-gts對於Balb/c小鼠體重的影響----110
玖、參考文獻----111
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