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Bioinformatic and Modelling Approaches for a System-Level Understanding of Oxidative Stress Toxicity Elias Zgheib

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Bioinformatic and Modelling Approaches for a System-Level Understanding of Oxidative Stress Toxicity Elias Zgheib Bioinformatic and modelling approaches for a system-level understanding of oxidative stress toxicity Elias Zgheib To cite this version: Elias Zgheib. Bioinformatic and modelling approaches for a system-level understanding of oxidative stress toxicity. Quantitative Methods [q-bio.QM]. Université de Technologie de Compiègne, 2018. English. NNT : 2018COMP2464. tel-02088169 HAL Id: tel-02088169 https://tel.archives-ouvertes.fr/tel-02088169 Submitted on 2 Apr 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Par Elias ZGHEIB Bioinformatic and modelling approaches for a system- level understanding of oxidative stress toxicity Thèse présentée pour l’obtention du grade de Docteur de l’UTC Soutenue le 18 décembre 2018 Spécialité : Bio-ingénierie et Mathématiques Appliquées : Unité de Recherche Biomécanique et Bio-ingénierie (UMR-7338) D2464 BIOINFORMATIC AND MODELLING APPROACHES FOR A SYSTEM-LEVEL UNDERSTANDING OF OXIDATIVE STRESS TOXICITY A THESIS SUBMITTED TO THE UNIVERSITE DE TECHNOLOGIE DE COMPIEGNE SORBONNE UNIVERSITES LABORATOIRE DE BIO-MECANIQUE ET BIOINGENIERIE UMR CNRS 7338 – BMBI 18TH OF DECEMBER 2018 For the degree of Doctor Spécialité : Bio-ingénierie et Mathématiques Appliquées Elias ZGHEIB SUPERVISED BY Prof. Frédéric Y. BOIS JURY MEMBERS Mme. Karine AUDOUZE Rapporteur Mr. Vincent FROMION Rapporteur Mme. Cécile LEGALLAIS Examiner Mr. Maxime CULOT Examiner Mr. Frédéric Y. BOIS Supervisor TABLE OF CONTENTS Table of Contents ..................................................................................................................... 2 Acknowledgements ................................................................................................................... 5 List of Abbreviations ................................................................................................................ 7 List of Figures ........................................................................................................................... 9 List of Tables ........................................................................................................................... 14 1 Introduction ..................................................................................................................... 16 2 Bibliography .................................................................................................................... 24 2.1 Toxicology ................................................................................................................................. 24 2.1.1 Definition of Toxicity ..................................................................................................... 24 2.1.2 Predictive Toxicology: Prevention ................................................................................. 24 2.1.3 Birth of Toxicology ......................................................................................................... 25 2.1.4 Limitations of Traditional Toxicology ............................................................................ 25 2.1.5 A Paradigm Shift in Toxicology ...................................................................................... 26 2.1.6 Modern Toxicology ........................................................................................................ 33 2.2 Biology Underlying Toxicology ................................................................................................. 38 2.2.1 Oxidative Stress, Nrf2 and some Associated Pathways ................................................ 39 2.2.2 Systems Biology – SB ..................................................................................................... 45 2.2.3 Adverse Outcome Pathways – AOP ............................................................................... 47 2.3 Mathematical Considerations .................................................................................................. 49 2.3.1 Ordinary Differential Equations – ODE – Systems ......................................................... 49 2.3.2 Michaelis-Menten – MM – Kinetics............................................................................... 51 2.3.3 The Hill Equation ........................................................................................................... 53 2.3.4 Bayesian Statistical Tools ............................................................................................... 57 2.3.5 Model’s Calibration ....................................................................................................... 61 3 Construction of Systems Biology Model of Nrf2 Control of Oxidative Stress .......... 64 3.1 Starting Models ........................................................................................................................ 64 3.1.1 The model of ‘Hamon et al. (2014)’ ............................................................................... 64 3.1.2 The model of ‘Geenen et al. (2012) and Reed et al. (2008)’ .......................................... 65 3.2 Methods ................................................................................................................................... 66 3.2.1 Remodelling Hamon’s model ........................................................................................ 66 3.2.2 Assembling two models ................................................................................................. 71 3.3 Results ...................................................................................................................................... 74 4 SB and other Tools for the Development of quantitative AOPs ................................. 78 4.1 Study Context ........................................................................................................................... 78 4.2 Methods ................................................................................................................................... 80 2 4.2.1 Experimental data ......................................................................................................... 80 4.2.2 Chronic Kidney Disease – CKD – AOP ............................................................................ 81 4.2.3 Dose-Response based qAOP .......................................................................................... 82 4.2.4 Bayesian Network – BN – qAOP .................................................................................... 83 4.2.5 The Systems Biology – SB – Model ................................................................................ 85 4.2.6 Parameter Estimation .................................................................................................... 87 4.2.7 Uncertainty propagation ............................................................................................... 89 4.2.8 Software ........................................................................................................................ 89 4.3 Results ...................................................................................................................................... 90 4.3.1 Dose-Response based qAOP Model .............................................................................. 90 4.3.2 Bayesian Network – BN – qAOP Model ......................................................................... 93 4.3.3 System biology – SB – Model ........................................................................................ 95 4.4 Discussion ............................................................................................................................... 101 4.5 Conclusion .............................................................................................................................. 107 5 Investigation of Nrf2, AhR and ATF4 Activation in Toxicogenomic Databases .... 109 5.1 The General Approach............................................................................................................ 109 5.2 Material and Methods ............................................................................................................ 111 5.2.1 Generation of Target Gene Lists .................................................................................. 111 5.2.2 Construction of a Chemical-Effects Transcriptomics Database................................... 112 5.2.3 Data Sources ................................................................................................................ 114 5.2.4 Bioinformatics Methods .............................................................................................. 116 5.2.5 Pathway’s Signature-Based Prioritization of Chemicals .............................................. 120 5.3 Results .................................................................................................................................... 123 5.3.1 Pathways’ Global Signatures ....................................................................................... 123 5.3.2 Pathways’ Stratified
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