High-Field NMR Metabolomics : Phenotyping the Metabolic Complexity from Humans to Cells

• Main Author: Pontoizeau, Clément
• Language: ENG
• Published: Ecole normale supérieure de lyon - ENS LYON 2012
• Subjects: [CHIM:OTHE] Chemical Sciences/Other; [CHIM:OTHE] Chimie/Autre; Metabolomics; Metabonomics; NMR; Molecular epidemiology; Cancer; Model organism; Caenorhabditis elegans; Biostatistics
• Online Access: http://tel.archives-ouvertes.fr/tel-00918143; http://tel.archives-ouvertes.fr/docs/00/91/81/43/PDF/PONTOIZEAU_Clement_2012_These.pdf

This thesis is dedicated to developments and applications of metabolomics, exploiting high field NMR spectroscopy. The first part is dedicated to a general presentation of metabolomics. We also report results about the introduction of reduced dimensionality techniques for the characterization of complex mixtures, coined targeted projection NMR spectroscopy. The second part of this manuscript reports results about three different metabolomic studies carried out in human populations. The first analysis demonstrates the suitability for metabolomics of serum samples collected in the framework of the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The second study investigates a serum metabolic signature of metastatic breast cancer. The last analysis establishes potential plasma metabolic signatures for different liver pathologies, like hepatocellular carcinoma. The third part of this thesis is dedicated to the characterization of various model organisms. The first study presents a characterization of plasma and urine metabolic differences between four rat strains commonly used as controls in genetic studies. In the second study, we investigate the effects of physiological aging in Caenorhabditis elegans (C. elegans) and observe that dietary restriction buffers metabolic changes associated with aging. We further identify that perturbations in phosphocholine metabolism correlate with life expectancy. The third analysis of this part characterizes the ahr-1 C. elegans mutant, showing strong metabolic changes in ahr-1 mutants, which suggest an involvement in development and aging processes. We finally investigate in the last study the effects at the metabolic level of the interaction between an endogenous protein E4F1 and a viral protein HBx in liver cells infected by hepatitis B virus.