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研究生： 鄭玉珮
Yu-Pei Cheng
論文名稱： 脂筏在非洲眼鏡蛇心臟毒蛋白作用於人類嗜中性白血球之角色
The Role of Lipid Raft on Toxin γ Action at Human Neutrophil
指導教授： 吳文桂
Wen-Guey Wu
口試委員:
學位類別： 碩士
Master
系所名稱： 生命科學暨醫學院 - 生物資訊與結構生物研究所
Institute of Bioinformatics and Structural Biology
論文出版年： 2004
畢業學年度： 92
語文別： 中文
論文頁數： 70
中文關鍵詞： 脂筏 、中東非眼鏡蛇 、嗜中性白血球
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    • 本實驗室過去的研究發現，嗜中性白血球對於中東非眼鏡蛇之心臟毒素Toxin γ (Tγ)具有很強的耐受性，但是在短時間內受到Tγ的刺激下，嗜中性白血球的肌動蛋白會聚集成聚合體，造成嗜中性白血球的形變；前述Tγ對嗜中性白血球所造成之影響，並非一種趨化性作用 (從趨化盤的實驗證明Tγ不會引起嗜中性白血球形變而穿透分隔膜)，顯然地，Tγ是以不同於fMLP(化學趨化物)之路徑，來引發細胞的肌動蛋白產生聚集化。為探討Tγ在嗜中性白血球膜上的作用機制，我們用介面活性劑(detergent)將細胞膜加以切割後，以蔗糖梯度(sucrose gradient)加以區分為九個部分(DRM extraction)，並用免疫染色法鑑定每個部分的特定蛋白含量，再以薄膜層析碘染法鑑定每個部分的脂質成分；結果發現Tγ在細胞膜上所分佈的位置和磷化脂質(sulfatide)的位置相似，位於脂筏區域(raft)，且分布在蔗糖梯度分離部分的前端，而受到刺激的嗜中性白血球之肌動蛋白分布和控制組(僅以緩衝液處理)及對照組(100nM fMLP)明顯不同，因此我們可以推論Tγ會作用在嗜中性白血球之脂筏區域，和磷化硫脂分佈在同一區域，並因此造成細胞肌動蛋白分佈的變動，由於在免疫染色法上同時觀測到：受到Tγ刺激的的嗜中性白血球會有Rac/Cdc42 family的蛋白表現，因此進一步推論造成肌動蛋白聚集化之過程可能是透過Rac/Cdc42之訊號傳遞，所造成細胞骨架之變動。至於Tγ和脂筏的結合，我們則是藉由免疫覆蓋技術(immunooverlay)發現Tγ和磷化硫脂在體外(in vitro)會有鍵結之現象，且經由免疫遮蔽效應證實：若將細胞表面上的磷化硫脂以其專一抗體鍵結以遮蔽其效應，則由Tγ所引起的細胞毒殺率將隨所加之磷化硫脂抗體濃度增加而遞減。這可以解釋為何Tγ分佈的位置恰與磷化硫脂相似及其生理作用。總結而言，Tγ可能是藉由和磷化硫脂的鍵結和牽引，而坐落到嗜中性白血球的脂筏端上作用，進行毒殺細胞之後續動作，而在坐落到脂筏區之前後的時間點(兩者皆有可能)，引發Rac/Cdc42之訊號傳遞，造成胞內肌動蛋白之單體聚集(actin polymerization)造成嗜中性白血球之形變。

    一、序論 1.蛇毒---------------------------------------------------7 2.心臟毒素 ----------------------------------------------9 2.1.心臟毒素簡介-----------------------------------------9 2.2.Tγ簡介-----------------------------------------------11 3.嗜中性白血球簡介---------------------------------------12 3.1.嗜中性白血球-----------------------------------------16 3.2.化學趨化作用-----------------------------------------16 3.3.肌動蛋白---------------------------------------------19 4.脂質(lipid)介紹----------------------------------------22 4.1.細胞膜上之脂質分佈---------------------------------- 22 4.1.1.脂質脂筏之定義與脂筏端（raft domain）介紹----------23 4.1.2.磷化硫脂（sulfatide）介紹--------------------------25 4.2.脂質端（lipid domain）之簡介-------------------------27 4.3.脂質脂筏（lipid raft）之簡介-------------------------28 4.3.1.脂質脂筏之定義與脂筏端（raft domain）介紹----------28 4.3.2.磷化硫脂（sulfatide）介紹--------------------------32 4.3.3.Rac、Rho在脂筏上傳遞訊號造成肌動蛋白之變動---------34 二、實驗材料及方法---------------------------------------37 1.材料---------------------------------------------------37 2.方法---------------------------------------------------38 2.1.蛇毒的製備-------------------------------------------38 2.2.嗜中性白血球之分離---------------------------------- 38 2.3.細胞毒性測定-----------------------------------------40 2.4.Detergent-resistant membrane domain萃取--------------41 2.5.SDS-PAGE及西方點墨法鑑定-----------------------------42 2.5.1.聚丙烯醯胺膠體(SDS-PAGE--------------------------- 42 2.5.2.西方點墨法(Western Blotting)---------------------- 44 2.6.用薄膜層析法鑑定脂質成分---------------------------- 45 2.6.1.展開式薄墨層析法---------------------------------- 45 2.6.2.點墨法(Dot-Plot) ----------------------------------46 2.7.共軛焦顯微鏡之免疫染色鑑定-------------------------- 46 三、結果-------------------------------------------------48 1.Tγ對嗜中性白血球的肌動蛋白之分佈和Raft間之關係-------- 48 1.1.BCA assay分析----------------------------------------48 1.2.西方點墨法分析---------------------------------------48 1.3.薄膜層析法分析---------------------------------------50 1.4.共軛焦顯微鏡分析-------------------------------------51 2.Sulfatide的角色----------------------------------------53 2.1.免疫覆蓋技術鑑定硫化磷脂和Tγ間之結合作用------------ 53 2.2.以抗體遮蔽效應探討硫化磷脂對Tγ之毒理影響------------ 54 四、討論-------------------------------------------------55 五、參考文獻---------------------------------------------65

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