Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/22174
標題: 結合液相等電點聚焦分離與質譜技術的膜蛋白體定量平台
Quantitative Membrane Proteomic Strategy Integrating Solution IEF Separation Technology and Mass Spectrometry
作者: 施宏達
Shih, Hung-Ta
關鍵字: 分離液相胜肽的等電點分離聚焦技術;OFFGEL;同位素標記相對和絕對定量法;免標定定量法;膠體輔助蛋白質水解法;isobaric tag for relative and absolute quantitation;iTRAQ;Label-free quantitation;Gel-assisted digestion
出版社: 分子生物學研究所
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摘要: 
膜蛋白質的異常表現已被證實與人類疾病和癌症疾病狀態是息息相關的。針對膜蛋白進行全面性的定量分析,可以促使我們更深入了解細胞調控的機制,讓我們有機會找出有可能的生物標記因子 (Biomarker),以提供疾病的診斷或是治療用途。為了得到更有效率的膜蛋白體分析,在樣品進入質譜分析前,降低蛋白或胜肽樣品複雜度的前處理步驟,對膜蛋白體的全面性鑑定與定量就顯得特別重要。
在此論文中,我們提出一個以分離技術為基礎的膜蛋白體定量技術,此平台結合了膠體輔助蛋白質水解法、同位素標記相對和絕對定量法(isobaric tag for relative and absolute quantitation, iTRAQ)或免標定定量法(Label-free quantitation)、分離液相胜肽的等電點分離聚焦技術 (OFFGEL)、液相層析串聯質譜儀分析以及生物資訊。由細胞和組織分析結果顯示,相較於強陽離子交換層析(Strong cation exchange chromatography),OFFGEL可提供較高解析的胜肽分離效果:接近90%的胜肽可被分離在少於兩個區間當中。結合OFFGEL與iTRAQ定量法或免標定定量法,這兩個系統可提供相近的精準度(在細胞樣品中:免標定定量法的平均值為0.87,iTRAQ定量法為1.02;在組織樣品中:免標定定量法的平均值為0.99)以及誤差範圍(在細胞樣品中:免標定定量法的標準偏差為0.65,iTRAQ定量法為為0.19;在組織樣品中:免標定定量法的標準偏差為1.08)。
在本論文的第二部分,我們將此策略應用在餵食高脂肪飼料老鼠的脂肪細胞上,以探討葡萄糖耐受異常和第二型糖尿病中相關的表現量改變的膜蛋白質。在結果中,總共有841個蛋白質可被定量,並且在餵食2、7、8個月的老鼠脂肪細胞中發現260、331和115個蛋白質具有異常的表現量。在這些變異蛋白質中,cluster of differentiation 36 (CD36)、fatty acid transporter (FATP)、acyl-CoA synthetase和 Carnitine O-palmitoyltransferase 1 (CPT1)都曾經被報導和脂肪酸吸收及代謝是有關的。我們提出的定量分析平台不僅能有效的找尋針對葡萄糖耐受異常的治療標靶蛋白質,更可以幫助我們了解形成第二型糖尿病的分子機制。

Abnormal expressions of membrane proteins have been linked to variety of human diseases. Comprehensive quantitative membrane proteomics will facilitate our understanding of their roles in regulating biological functions and discover potential biomarkers for diagnostic, prognostic or therapeutic use. To obtain an efficient proteome-scale analysis of membrane proteome, pre-fractionation of proteins/peptides prior to mass spectrometric detection is crucial for comprehensive identification and quantification of membrane proteins.
In this study, we proposed a fractionation-based strategy which integrates gel-assisted digestion, isobaric tag for relative and absolute quantitation (iTRAQ) or label-free method, peptide-level OFFGEL fractionation, LC-MS/MS analysis, and bioinformatics computation for quantitative membrane proteomics. Based on the results on cell and tissue analysis, the OFFGEL system shows higher resolution for peptide separation than strong cation exchange chromatography: Near 90% of peptides can be focused in less than two fractions. Combining OFFGEL with iTRAQ or label-free quantitation, the two platforms provide similar accuracy (for cell line sample: mean = 0.87 in label-free quantitation and 1.02 in iTRAQ quantitation; for tissue sample: mean = 0.99 in label-free quantitation) and narrow variation (for cell line sample: standard deviation = 0.65 in label-free quantitation and 0.19 in iTRAQ quantitation; for tissue sample: standard deviation = 1.08 in label-free quantitation).
In the second part of the thesis, we applied this new strategy OFFGEL fractionation and iTRAQ labeling to analyze expression levels of membrane proteins of adipocyte from high-fat diet mice to study the mechanism of impaired glucose tolerance in type 2 diabetes. A total of 841 proteins were quantified and there were 260, 332, and 115 differentially expressed proteins after the mice were fed with high-fat diet for 2, 7, and 8 months, respectively. Some of these proteins, including cluster of differentiation 36 (CD36), fatty acid transporter (FATP), acyl-CoA synthetase, and carnitine O-palmitoyltransferase 1 (CPT1) had been reported to be involved in the fatty acid metabolism. Pathway analysis revealed the up-regulation of fatty acid metabolism and down-regulation of glucose metabolism. Our method not only demonstrated its power on discovery of potential targets for impaired glucose tolerance but may help to shed light on the molecular mechanism underlying formation of type 2 diabetes.
URI: http://hdl.handle.net/11455/22174
其他識別: U0005-2308201014324400
Appears in Collections:分子生物學研究所

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