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Détermination D'une Signature Transcriptionnelle De L'état De UNIVERSITÉ DE NANTES FACULTE DE MÉDECINE DÉTERMINATION D’UNE SIGNATURE TRANSCRIPTIONNELLE SANGUINE DU DEVENIR À LONG TERME DU GREFFON DE PATIENTS RECEVANT UNE ALLOGREFFE RÉNALE. THESE DE DOCTORAT École doctorale : CHIMIE-BIOLOGIE Discipline : SCIENCES DE LA VIE ET DE LA SANTE Spécialité : IMMUNOLOGIE Présentée et soutenue publiquement par Christophe BRAUD le 20 décembre 2007, devant le jury ci-dessous : Rapporteurs : Eric THERVET ; Professeur ; Paris Alberto SANCHEZ-FUEYO ; Docteur ; Barcelone Examinateurs : Dominique BAETEN ; Professeur ; Amsterdam Georges GUELLAEN ; Directeur de recherche ; Paris Jean-Paul SOULILLOU ; Professeur ; Nantes Directeur de thèse : Dr. Sophie BROUARD ; Chargé de recherche ; Nantes « Ce n’est pas parce que les choses sont difficiles que nous n’osons pas, c’est parce que nous n’osons pas qu’elles sont difficiles » Sénèque « Le futur appartient à ceux qui croient à la beauté de leurs rêves » Eleanor Roosevelt Sommaire Sommaire Sommaire ................................................................................................................................... 3 Abréviations ............................................................................................................................... 5 Liste des figures ......................................................................................................................... 6 Liste des tables ........................................................................................................................... 7 Avant-propos .............................................................................................................................. 8 Introduction ............................................................................................................................. 11 1. Le rejet de greffe..................................................................................................................... 12 1.1 Le rejet hyperaigu ....................................................................................................................... 14 1.2 Le rejet aigu ................................................................................................................................. 14 1.3 Le rejet chronique ....................................................................................................................... 15 2. La tolérance « opérationnelle » ............................................................................................. 16 3. Recherche de « Biomarqueurs » ........................................................................................... 21 3.1. Définition d’un « biomarqueur » ............................................................................................... 21 3.2. Choix de l’échantillon biologique ............................................................................................... 22 3.2.1 La biopsie ................................................................................................................................. 22 3.2.2. L’urine ...................................................................................................................................... 22 3.2.3. Le sang ..................................................................................................................................... 23 3.3. « Biomarqueurs » et transplantation rénale ............................................................................. 24 3.3.1. Biomarqueurs et rejet aigu ........................................................................................................ 24 3.3.1.1. Spectrométrie de masse ................................................................................................... 24 3.3.1.2. Puces à ADN ................................................................................................................... 25 3.3.2. Biomarqueurs et rejet chronique ............................................................................................... 26 3.3.2.1. Spectrométrie de masse ................................................................................................... 26 3.3.2.2. Puces à ADN ................................................................................................................... 26 3.3.3. Biomarqueurs et tolérance « opérationnelle » .......................................................................... 27 4. Contexte méthodologique des puces à ADN ......................................................................... 28 4.1 Introduction ................................................................................................................................. 28 4.1.1 Historique ................................................................................................................................. 28 4.1.2 Principe des puces à ADN et analyse du transcriptome ........................................................... 31 4.2 Hybridation des puces à ADN .................................................................................................... 33 4.2.1 Préparation des échantillons ..................................................................................................... 33 4.2.2 Marquage .................................................................................................................................. 33 4.2.3 Hybridation ............................................................................................................................... 34 4.3 Acquisition des données .............................................................................................................. 34 4.3.1 Acquisition des images ............................................................................................................. 34 4.3.2 Analyse des images .................................................................................................................. 35 4.4 Transformation des données ...................................................................................................... 36 4.4.1 Notation et représentation des données .................................................................................... 37 4.4.2 Filtration des données ............................................................................................................... 38 4.4.3 Normalisation des données ....................................................................................................... 39 4.4.3.1 Méthode des gènes invariants ......................................................................................... 39 4.4.3.2 Normalisation spatiale .................................................................................................... 40 4.4.3.3 Normalisation par méthode Lowess ................................................................................ 41 4.4.3.4 Réajustement (scaling) .................................................................................................... 41 4.4.4 Elimination des valeurs aberrantes ........................................................................................... 42 4.5. Analyses des résultats .................................................................................................................. 42 4.5.1 Stockage des données ............................................................................................................... 42 4.5.2. Détection des gènes différentiellement exprimés ..................................................................... 43 4.5.3. Choix du seuil de significativité ............................................................................................... 45 Sommaire 4.5.3.1. Erreur FWER .................................................................................................................. 45 4.5.3.2. Erreur FDR ..................................................................................................................... 46 4.5.4. Regroupement hiérarchique des données d’expressions ........................................................... 46 4.5.4.1. Classification non-supervisée ......................................................................................... 47 4.5.4.2. Classification supervisée................................................................................................. 49 4.5.5. Interprétations des données ...................................................................................................... 50 4.5.5.1. GO : Gene Ontology ....................................................................................................... 51 4.5.5.2 Banques de données ........................................................................................................ 51 4.5.5.3. Confrontation, combinaison et recoupement des données .............................................. 52 4.5.6. Puces et art ! ............................................................................................................................. 53 5. Objectifs .................................................................................................................................. 54 Résultats ................................................................................................................................... 56 1. Article I ......................................................................................................................................... 57 1.1.
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