臺灣博碩士論文加值系統

Lipid rafts 是細胞膜上的特化結構，其特性為富含cholesterol，sphingolipids與glycophosphatidylinositol-anchored proteins。在之前的研究指出，lipid rafts在物質運輸與訊息傳遞中扮演重要的角色。Lipid rafts蛋白質體上的研究大部分是利用非膠體的方法，例如使用液相層析與質譜儀。相形之下，二維電泳的方法則較少被利用來分析lipid rafts蛋白質體，儘管它能夠在ㄧ片膠上分離上千個蛋白質。本論文的研究目標主要是爲了發展一個基於二維電泳的高解析度的分離策略及結合串聯式質譜儀來建立lipid rafts的蛋白質圖譜。爲了利用二維電泳來分離lipid rafts的成分，我們以THP-1細胞為實驗模型，首先利用density gradient將lipid rafts分離出來，並使用多種以CHAPS為基礎的detergent組合來試驗二維電泳分離的效果。經蛋白質圖譜解析度與蛋白質點的數目分析結果顯示發現使用結合ASB-14與CHAPS來分離lipid rafts的效果較好。在二維電泳膠片上已利用串聯式質譜儀鑑定出17個蛋白質點，包括actin-gamma1、alpha-tubulin、G-beta1、RhoA、Rab、heat shock cognate protein、P58、GRP78以及intracellular chloride channels。由於lipid rafts與訊息傳遞有關，所以我們利用已建立的二維電泳方法來探討fractalkine處理的THP-1細胞在lipid rafts成分的變化。在lipid rafts二維電泳圖譜的影像分析顯示細胞經fractalkine刺激後導致12個蛋白質的表現出現差異。其中有6個蛋白質點的表現增加與6個蛋白質點的表現被抑制。利用二維電泳與質譜儀技術，本論文已成功地建立一個高解析度的lipid rafts蛋白質體分析平台。以蛋白質體學為基礎的策略不僅可以探索許多未知的lipid rafts蛋白質身份並且也進一步提供與lipid rafts相關的訊息傳遞路徑的了解。

Lipid rafts are specialized microdomain of plasma membrane characterized by its enrichment of cholesterol, sphingolipids, and GPI-anchored proteins. Previous studies have indicated that lipid rafts play an important role in vecicular trafficking and receptor-mediated signal transduction. To date, the studies on the lipid rafts proteome mostly utilized nongel-based methods, such as a combination of liquid chromatrography and mass spectrometry. In contrast, lipid rafts proteins are poorly resolved by two-dimensional gel electrophoresis (2-DE), despite its ability to separate thousands of proteins in one gel. The aim of this study is to develop a high resolution separation strategy based on 2-DE and to couple with tandem mass spectrometry to profile the lipid rafts. First, the lipid rafts in THP-1 cells were separated by density gradient centrifugation and further confirmed by immunoblotting analysis using markers of lipid rafts and ornagelle’s membrane. For separation of raft components by 2-DE, a variety of detergents were tested. The results showed that the raft components are better separated by a combination of ASB-14 and CHAPS with respect to the pattern and the number of protein spots resolved. The identities of 17 spots have also been determined by mass spectrometry, including signaling molecules, cytoskeleton proteins, vesicular trafficking, and endoplasmic reticulum components. As lipid rafts are involved in transmembrane signaling, the established 2-DE approach was applied to explore the change of raft components in control and fractalkine-treated THP-1 cells. Image analysis of the 2D profiles indicated that there are 12 differentially expressed protein spots in the lipid rafts fraction of fractalkine-treated cells. Among them, 6 spots are up-regulated and 6 down-regulated. In summary, we have successfully established a strategy using high resolution 2-DE to separate the lipid rafts components. Coupling with protein identification by mass spectrometry, the 2DE-based strategy will not only be useful to establish the lipid rafts proteome but also lead to a better understanding of raft-associated signaling network.

摘要……………………………………………………………………………………iv
誌謝……………………………………………………………………………………vi
目次……………………………………………………………………………………vii
表目錄…………………………………………………………………………………ix
圖目錄…………………………………………………………………………………x
縮寫對照表……………………………………………………………………………xi
第一章 研究動機與目的……………………………………………………………1
第二章 緒論…………………………………………………………………………3
2-1 Lipid rafts之簡介……………………………………………………3
2-1.1 Lipid rafts的結構…………………………………………3
2-1.2 Lipid rafts markers……………………………………5
2-1.3 Lipid rafts的功能…………………………………………5
2-2 Caveolae之簡介………………………………………………………7
2-2.1 Caveolae的結構……………………………………………7
2-2.2 Caveolae的功能……………………………………………9
2-3 萃取lipid rafts的技術……………………………………………9
2-4 蛋白質體學……………………………………………………………10
2-4.1 蛋白質二維電泳……………………………………………11
2-4.2 蛋白質鑑定…………………………………………………11
2-5 Lipid rafts蛋白質圖譜的研究……………………………………12
2-6 Fractalkine之簡介…………………………………………………14
2-6.1 Fractalkine的結構………………………………………14
2-6.2 Fractalkine的sigaling pathways…………………18
2-6.3 Fractalkine的功能………………………………………18
2-7 THP-1 monocytic cell line……………………………………19
第三章 材料與方法………………………………………………………………21
3-1 材料……………………………………………………………………21
3-1.1 細胞株………………………………………………………21
3-1.2 藥品試劑……………………………………………………21
3-1.2.1 細胞培養試劑…………………………………21
3-1.2.2 ㄧ般藥品與試劑………………………………21
3-1.2.3 抗體……………………………………………22
3-2 研究方法………………………………………………………………23
3-2.1 細胞培養……………………………………………………23
3-2.2 Lipid rafts的萃取………………………………………23
3-2.3 等電點電泳（isoelectric focusing, IEF）………24
3-2.4 SDS-PAGE …………………………………………………24
3-2.5 銀染（silver staining)………………………………24
3-2.6 二維電泳膠片影像分析比對………………………………25
3-2.7 蛋白質鑑定 …………………………………………………25
3-2.8 西方墨點法（Western blotting）……………………25
第四章 結果與討論………………………………………………………………26
4-1 THP-1細胞lipid rafts的萃取……………………………………26
4-2 THP-1細胞lipid raftsㄧ維蛋白質圖譜…………………………30
4-3 THP-1細胞lipid rafts二維電泳圖譜……………………………41
4-4 Fractalkine影響之THP-1細胞的lipid rafts蛋白質圖譜……54
4-5 結論……………………………………………………………………54
參考文獻……………………………………………………………………………60

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