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Lipidomics Investigations in Cell Biology Yang Yu Yang Yu PhD Thesis Lipidomics Investigations in Cell Biology International Doctoral School in Biomolecular Sciences 26th cycle Lipidomics Investigations in Cell Biology PhD thesis of: Yang Yu Centre for Integrative Biology (CIBIO) Academic Year 2012 – 2013 Tutor: Prof. Graziano Guella Bioorganic Chemistry Laboratory (Dept. Physics) Advisors: Prof. Paolo Macchi (CIBIO), Dr. Urska Vrhovsek (FEM) 1 Yang Yu PhD Thesis Lipidomics Investigations in Cell Biology 'Declaration of Authorship: I (Yang Yu) confirm that this is my own work and the use of all material from other sources has been properly and fully acknowledged.' Tutor: Prof. Graziano Guella PhD Candidate: Yang Yu 2 Yang Yu PhD Thesis Lipidomics Investigations in Cell Biology Abbreviations ADMEM Advanced-Dulbecco’s Modified Essential Medium CAD Collision gas CE Collision Energy Chol Cholesterol CID Collision-Induced Dissociation CUR CURtain gas CXP Collision Cell Exit Potential DAG Diglycerides DESI Desorption Electrospray Ionization DHAP DiHydroxyAcetonePhosphate DHAPAT DiHydroxyAcetonePhosphate AcylTransferase DLPC 1,2-Dilauroyl-sn-glycero-3-PhosphoCholine DMEM Dulbecco’s Modified Essential Medium DOPA 1,2-Dioleoyl-sn-glycero-3-Phosphate DOPC 1,2-Dioleoyl-sn-glycero-3-PhosphoCholine DOPS 1,2-Dioleoyl-sn-glycero-3-Phospho-L-Serine DP Declustering Potential DSPG 1,2-Dioctadecanoyl-sn-glycero-3-Phospho-(1'-rac-Glycerol) EI Electron Ionization EIC Extracted Ion Chromatogram EP Entrance Potential ePC plasmanyl (or ether) PC ER Endoplasmic Reticulum ESI Electrospray Ionization FBS Fetal Bovine Serum FP Focusing Potential GC-MS Gas Chromatography–Mass Spectrometry GL GlycoLipids GlcCer GlucosylCeramide GPL GlyceroPhosphoLipids GSL GlycoSphingoLipids 1H DQCOSY Double Quantum COherence SpectroscopY 1H-13C HMBC proton-carbon Multiple-Bond Correlation 1H-13C HSQC proton-carbon Single Quantum Correlation HIF 1-a Hypoxia-Inducible Factor 1-alpha HIF Hypoxia-Inducible Factor HPLC High Performance Liquid Chromatography IS IonSpray 3 Yang Yu PhD Thesis Lipidomics Investigations in Cell Biology LPC Lyso PhosphoCholines LPE Lyso PhosphoEthanolamines LPL Lyso PhosphoLipids MALDI TOF MS Matrix-Assisted Laser Desorption Ionization Time-Of-Flight Mass spectrometer MS Mass Spectrometry MUFA Mono-Unsaturated Fatty Acid MVDA MultiVariate Data Analysis NEB NEBulizer gas NLS Neutral Loss Scanning NMR Nuclear Magnetic Resonance NPLC Normal Phase Liquid Chromatography OPLS-DA Orthogonal Projections to Latent Structures-Discriminant Analysis PA Phosphatidic Acids PAF Platelet-Activating Factor PC PhosphoCholines PC1 Principal Component 1 PC2 Principal Component 2 PCA Principal Component Analysis PE PhosphoEthanolamines PG PhosphoGlycerols PI PhosphoInositols PIS Precursor Ion Scanning PL PhosphoLipids PLS-DA Partial Least Squares Discriminant Analysis pPC plasmenyl (or vinyl-ether) PC PS PhosphoSerines PUFA Poly-Unsaturated Fatty Acid QQQ MS Triple Quadruple Mass Spectrometer REIMS Rapid Evaporative Ionization Mass Spectrometry RP-HPLC Reversed Phase High Performance Liquid Chromatography RTK Receptor Tyrosine Kinases S1P Sphingosine-1-Phophate SL SphingoLipids TAG Triglycerides TEM TEMperature TIC Total Ion Chromatogram TOCSY TOtally Correlated SpectroscopY UI Unsaturation Index UVDA UniVariate Data Analysis VIP Variable Influence on Projection 4 Yang Yu PhD Thesis Lipidomics Investigations in Cell Biology Table of Contents Chapter 1. Abstract ........................................................................................................................... 7 Chapter 2. Introduction .................................................................................................................. 9 2.1 Lipids and lipidomics .................................................................................................................... 9 2.2 NMR and Mass spectrometry .................................................................................................. 15 2.3 Sample preparation for lipidomics analysis......................................................................... 20 2.4 Lipidomics data processing ...................................................................................................... 21 2.5 Aim of the thesis ......................................................................................................................... 23 2.6 References .................................................................................................................................... 24 Chapter 3. A lipidomics investigation of the induced hypoxia stress on HeLa cells by using MS and NMR techniques .............................................................................. 28 3.1 Abstract ......................................................................................................................................... 28 3.2 Introduction ................................................................................................................................. 29 3.3 Materials and Methods ............................................................................................................. 33 Chemicals ............................................................................................................................................ 33 Cell culture and Hypoxia treatment .................................................................................................... 33 Immunocytochemistry and fluorescence microscopy ........................................................................ 33 Phospholipids extraction and sample preparation ............................................................................. 34 NMR measurements ........................................................................................................................... 35 Optimization of precursor ion scanning and neutral loss scanning for ESI MS/MS analysis .............. 35 HPLC-ESI MS/MS measurements ........................................................................................................ 36 Data processing ................................................................................................................................... 37 3.4 Results and discussion ............................................................................................................... 38 Cobalt (II) chloride induces hypoxia .................................................................................................... 38 NMR analysis of phospholipid classes................................................................................................. 39 Lipid class-specific (head groups) survey scans through MS/MS measurements .............................. 42 5 Yang Yu PhD Thesis Lipidomics Investigations in Cell Biology HeLa cellular phospholipids profiling and hypoxia-induced lipid alterations ..................................... 45 Multivariate analysis and individual potential marker analysis .......................................................... 49 Unsaturation Index analysis of each phospholipid class..................................................................... 54 3.5 Conclusions ................................................................................................................................... 56 3.6 Acknowledgments ...................................................................................................................... 58 3.7 Notes and References ............................................................................................................... 58 Chapter 4. Comparative Lipidomic studies of in vitro urinary bladder cancer models RT4 and T24: an investigation on urothelial metastasis ......................... 61 4.1 Abstract ......................................................................................................................................... 61 4.2 Introduction ................................................................................................................................. 61 4.3 Material and methods ............................................................................................................... 64 Chemicals ............................................................................................................................................ 64 Urothelial cell cultures of RT4 and T24 ............................................................................................... 64 Lipid extraction and sample preparation ............................................................................................ 65 NMR analysis and MS measurements ................................................................................................ 66 Data processing ................................................................................................................................... 66 4.4 Results and discussions ............................................................................................................. 67 Morphological comparison between RT4 and T24 ............................................................................. 67 1H-NMR and 31P-NMR analysis of RT4 and T24 lipid extracts ............................................................. 68 Cellular lipids comparison between RT4 and T24 via HPLC-ESI MS/MS measurements .................... 72 Multivariate analysis and individual potential marker analysis .......................................................... 78 Fatty acyl
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