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研究生:吳佩容
研究生(外文):Wu, Pei Jung
論文名稱:利用蛋白質交互作用及生物資訊資料庫重建訊號網路與定性模式分析
論文名稱(外文):Reconstruction Qf Signaling Transduction Pathway Via Protein-protein-interaction And Bioinformatical Database And Pathway Analysis Of Qualitative Model
指導教授:王逢盛
指導教授(外文):Wang, Feng Sheng
口試委員:周宜雄黃奇英錢玉樹
口試委員(外文):Chou, Yi-ShyongHuang, Chi-Ying F.Chien, Yu-Shu
口試日期:2012-06-28
學位類別:碩士
校院名稱:國立中正大學
系所名稱:化學工程研究所
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:143
中文關鍵詞:訊號傳遞網路蛋白質交互作用最小干擾集合
外文關鍵詞:signal transduction networkprotein protein interactionminimal intervention sets
相關次數:
  • 被引用被引用:0
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  • 下載下載:7
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此研究以Hela cell蛋白質交互作用為研究標的重建蛋白質網路,首先從鄰位蛋白質原位表現技術(in situ proximity ligation assay)取得Hela cell 557筆蛋白質交互作用對(positive protein protein interaction pair)。根據557筆交互作用,挑出其中108個與七個主要與癌症相關之信號路徑(EGF、PDGF、FGF、IGF、p38MAPK、Wnt/B-catenin、Sonic Hedgehog) 對應的物質,藉由Ingenuity Pathway Analysis 資料庫重建出包含此7個訊號路徑的蛋白質訊號傳遞網路,共包含70個節點及113條反應。將重建過後的訊號網路,比對557筆蛋白質交互作用,共有95筆交互作用對與重建出的訊號路徑重疊,其中46筆為直接作用對,22筆為間接作用,27筆為蛋白質模組中的作用對。
接著我們使用系統生物學軟體CellNetAnalyzer 來做細胞內模擬和分析訊號路徑。利用基本網路分析原理進行訊號傳遞路徑定性上分析,例如蛋白質間的相依矩陣、訊號途徑;再運用布林(boolean)邏輯網路運算,設定與細胞凋亡和增生的目標函數來計算最小干擾集合(minimal intervention set),並計算邏輯穩態(logical steady state)下的分析結果,進行生物意義上的討論,以提供生物學家設計疾病標靶的實驗方向。

In this search, we reconstruct protein signaling network to study the subject of Hela cell. First, we obtain 557 positive protein protein interactions(PPIs) pair of Hela cell from in situ proximity ligation assay. We select 108 proteins, belonging to 557 positive PPIs, corresponds with seven cancer-relating signaling pathway, such as EGF, PDGF, FGF, IGF, p38MAPK, Wnt/B-catenin and Sonic Hedgehog, which are searched by
IPA database, then we rebuild a signaling transduction network containing total of 70 protein nodes and 113 interaction edges. According to overlapping between 557 PPIs and signaling pathway, there are 95 PPIs overlapping interactions in the network, 46 for direct relationship, 22 for indirect relationship, 27 for PPI in protein module.
摘要 I
Abstract II
圖目錄 VII
表目錄 X
第一章 緒論 1
1.1 前言 1
1.2 文獻回顧 4
1.3 研究動機 7
1.4 組織章節 7
第二章 鄰位蛋白質原位表現技術與資料庫簡介 9
2.1 鄰位蛋白質原位表現技術 9
2.1.1 技術介紹 9
2.1.2 技術原理 9
2.1.3 蛋白質交互作用資料來源 11
2.2 資料庫簡介 12
2.2.1 Ingenuity Pathway Analysis (IPA) 13
2.2.2 Kyoto Encyclopedia of Genes and Genomes (KEGG) 14
2.2.3 Pathway Interaction Database (PID) 17
2.2.4 POINeT 18
2.2.5 資料庫間之比較 19
第三章 訊號傳遞網路重建 21
3.1 訊號傳遞路徑選取與生物意義 21
3.1.1 EGF 訊號傳遞路徑 22
3.1.2 PDGF訊號傳遞路徑 24
3.1.3 FGF訊號傳遞路徑 26
3.1.4 IGF訊號傳遞路徑 27
3.1.5 p38 MAPK訊號傳遞路徑 29
3.1.6 Wnt/B-catenin訊號傳遞路徑 31
3.1.7 Sonic Hedgehog訊號傳遞路徑 33
3.1.8 Apoptosis訊號傳遞路徑 35
3.1.9 Cell Cycle: G1/S訊號傳遞路徑 37
3.1.10 Cell Cycle: G2/M訊號傳遞路徑 39
3.2 訊號傳遞網路與蛋白質交互作用對疊合 40
3.2.1 訊號傳遞網路重建之節點說明 40
3.2.2 訊號傳遞網路疊合蛋白質交互用對 45
3.2.3 蛋白質交互作用中的crosstalk 51
3.2.4 重建後的訊號傳遞網路 52
第四章 網路模式定性分析工具與原理 54
4.1 網路模式定性分析軟體介紹 54
4.1.1 Process Modeling Tool (ProMoT) 54
4.1.2 CellNetAnalyzer (CNA) 56
4.2 網路模式定性分析原理 59
4.2.1 二元布林邏輯網路 59
4.2.2 網路模式分析 61
4.2.3 訊號網路的邏輯定性分析 69
第五章 結果與討論 74
5.1 訊號傳遞網路模式定性分析 74
5.1.1 網路拓蹼結構 74
5.1.2 訊號路徑分析 76
5.1.3 交互作用矩陣 80
5.1.4 最短距離矩陣 80
5.1.5 相依矩陣 84
5.1.6 同等階層物質 86
5.2 癌細胞的生理機制與標靶藥物 88
5.2.1 抵抗細胞凋亡 88
5.2.2 細胞持續增生 89
5.2.3 蛋白質的標靶藥物 90
5.3 抑制增生之計算分析 91
5.3.1 目標函數設定 91
5.3.2 最小干擾集合計算 92
5.3.3 邏輯穩定狀態分析 94
5.4 誘導凋亡之計算分析 97
5.4.1 目標函數設定 97
5.4.2 最小干擾集合計算 99
5.4.3 邏輯穩定狀態分析 102
5.5 藥物設計 105
第六章 結論與未來方向 107
6.1 結論 107
6.2 未來方向與建議 110
附錄一 111
附錄二 114
附錄三 117
附錄四 120
附錄五 122
參考文獻 125

[1]H. Kitano, "Computational systems biology," Nature, vol. 420, pp. 206-210, Nov 14 2002.
[2]M. W. Covert, et al., "Integrating metabolic, transcriptional regulatory and signal transduction models in Escherichia coli," Bioinformatics, vol. 24, pp. 2044-2050, Sep 15 2008.
[3]T. Pfeiffer, et al., "METATOOL: for studying metabolic networks," Bioinformatics, vol. 15, pp. 251-257, Mar 1999.
[4]D. R. Hyduke and B. O. Palsson, "Towards genome-scale signalling-network reconstructions," Nature Reviews Genetics, vol. 11, pp. 297-307, Apr 2010.
[5]Y. Yarden and M. X. Sliwkowski, "Untangling the ErbB signalling network," Nature Reviews Molecular Cell Biology, vol. 2, pp. 127-137, Feb 2001.
[6]K. Oda, et al., "A comprehensive pathway map of epidermal growth factor receptor signaling," Molecular Systems Biology, vol. 1, 2005.
[7]J. Saez-Rodriguez, et al., "A logical model provides insights into T cell receptor signaling," PLoS Computational Biology, vol. 3, pp. 1580-1590, Aug 2007.
[8]M. L. Schmitz, et al., "Signal integration, crosstalk mechanisms and networks in the function of inflammatory cytokines," Biochimica Et Biophysica Acta-Molecular Cell Research, vol. 1813, pp. 2165-2175, Dec 2011.
[9]L. H. Hartwell, et al., "From molecular to modular cell biology," Nature, vol. 402, pp. C47-C52, Dec 2 1999.
[10]H. Kitano, "Systems biology: A brief overview," Science, vol. 295, pp. 1662-1664, Mar 1 2002.
[11]B. B. Aldridge, et al., "Physicochemical modelling of cell signalling pathways," Nature Cell Biology, vol. 8, pp. 1195-1203, Nov 2006.
[12]S. Q. Zhang, et al., "Simulation study in Probabilistic Boolean Network models for genetic regulatory networks," International Journal of Data Mining and Bioinformatics, vol. 1, pp. 217-240, 2007.
[13]M. Kaufman, et al., "A logical analysis of T cell activation and anergy," Proceedings of the National Academy of Sciences of the United States of America, vol. 96, pp. 3894-3899, Mar 30 1999.
[14]M. A. Schaub, et al., "Qualitative networks: a symbolic approach to analyze biological signaling networks," BMC Systems Biology, vol. 1, Jan 8 2007.
[15]R. Samaga, et al., "The Logic of EGFR/ErbB Signaling: Theoretical Properties and Analysis of High-Throughput Data," PLoS Computational Biology, vol. 5, Aug 2009.
[16]R. Schlatter, et al., "ON/OFF and Beyond - A Boolean Model of Apoptosis," PLoS Computational Biology, vol. 5, Dec 2009.
[17]J. Saez-Rodriguez, et al., "Discrete logic modelling as a means to link protein signalling networks with functional analysis of mammalian signal transduction," Molecular Systems Biology, vol. 5, Dec 2009.
[18]O. Soderberg, et al., "Characterizing proteins and their interactions in cells and tissues using the in situ proximity ligation assay," Methods, vol. 45, pp. 227-232, Jul 2008.
[19]A. Jimenez-Marin, et al., "Biological pathway analysis by ArrayUnlock and Ingenuity Pathway Analysis," BMC Proc, vol. 3 Suppl 4, p. S6, 2009.
[20]C. F. Schaefer, et al., "PID: the Pathway Interaction Database," Nucleic Acids Research, vol. 37, pp. D674-D679, Jan 2009.
[21]S. A. Lee, et al., "POINeT: protein interactome with sub-network analysis and hub prioritization," Bmc Bioinformatics, vol. 10, Apr 21 2009.
[22]J. Reimand, et al., "g:Profiler--a web-based toolset for functional profiling of gene lists from large-scale experiments," Nucleic Acids Res, vol. 35, pp. W193-200, Jul 2007.
[23]M. Krull, et al., "TRANSPATH (R): an integrated database on signal transduction and a tool for array analysis," Nucleic Acids Research, vol. 31, pp. 97-100, Jan 1 2003.
[24]C. H. Heldin and B. Westermark, "Mechanism of action and in vivo role of platelet-derived growth factor," Physiological Reviews, vol. 79, pp. 1283-1316, Oct 1999.
[25]D. M. Ornitz and P. J. Marie, "FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease," Genes & Development, vol. 16, pp. 1446-1465, Jun 15 2002.
[26]P. P. Roux and J. Blenis, "ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions," Microbiology and Molecular Biology Reviews, vol. 68, pp. 320, Jun 2004.
[27]M. G. Wilkinson and J. B. A. Millar, "Control of the eukaryotic cell cycle by MAP kinase signaling pathways," Faseb Journal, vol. 14, pp. 2147-2157, Nov 2000.
[28]R. Nusse, "Wnt signaling and stem cell control," Cell Research, vol. 18, pp. 523-527, May 2008.
[29]Z. Song, et al., "Sonic Hedgehog Pathway Is Essential for Maintenance of Cancer Stem-Like Cells in Human Gastric Cancer," PLoS ONE, vol. 6, Mar 4 2011.
[30]S. Klamt, et al., "A methodology for the structural and functional analysis of signaling and regulatory networks," BMC Bioinformatics, vol. 7, Feb 7 2006.
[31]S. Mirschel, et al., "PROMOT: modular modeling for systems biology," Bioinformatics, vol. 25, pp. 687-689, Mar 1 2009.
[32]J. Saez-Rodriguez, et al., "Visual setup of logical models of signaling and regulatory networks with ProMoT," BMC Bioinformatics, vol. 7, Nov 17 2006.
[33]S. Klamt and A. von Kamp, "An application programming interface for CellNetAnalyzer," Biosystems, vol. 105, pp. 162-168, Aug 2011.
[34]S. Klamt, et al., "Structural and functional analysis of cellular networks with CellNetAnalyzer," BMC Systems Biology, vol. 1, Jan 8 2007.
[35]O. Hadicke, et al., "Metabolic network modeling of redox balancing and biohydrogen production in purple nonsulfur bacteria," BMC Systems Biology, vol. 5, Sep 25 2011.
[36]M. K. Morris, et al., "Logic-Based Models for the Analysis of Cell Signaling Networks," Biochemistry, vol. 49, pp. 3216-3224, Apr 20 2010.
[37]S. Klamt, et al., "Algorithmic approaches for computing elementary modes in large biochemical reaction networks," IEE Proceedings Systems Biology, vol. 152, pp. 249-255, Dec 2005.
[38]J. Stelling, et al., "Metabolic network structure determines key aspects of functionality and regulation," Nature, vol. 420, pp. 190-193, Nov 14 2002.
[39]M. Reth and T. Brummer, "Feedback regulation of lymphocyte signalling," Nature Reviews Immunology, vol. 4, pp. 269-277, Apr 2004.
[40]B. N. Kholodenko, "Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades," European Journal of Biochemistry, vol. 267, pp. 1583-1588, Mar 2000.
[41]R. Samaga, et al., "Computing Combinatorial Intervention Strategies and Failure Modes in Signaling Networks," Journal of Computational Biology, vol. 17, pp. 39-53, 2010.
[42]M. Kasper, et al., "GLI transcription factors: Mediators of oncogenic Hedgehog signalling," European Journal of Cancer, vol. 42, pp. 437-445, Mar 2006.
[43]J. W. Harbour and D. C. Dean, "The Rb/E2F pathway: expanding roles and emerging paradigms," Genes & Development, vol. 14, pp. 2393-2409, Oct 1 2000.
[44]D. Hanahan and R. A. Weinberg, "Hallmarks of Cancer: The Next Generation," Cell, vol. 144, pp. 646-674, Mar 4 2011.

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