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Cardiac Manifestations of Inherited Metabolic Disease Linked to Cellular Cardiac manifestations of inherited metabolic disease linked to cellular metabolism of vitamin B12 : study in two murine models of invalidation of Mtr and MMACHC genes Viola Jepchumba Kosgei To cite this version: Viola Jepchumba Kosgei. Cardiac manifestations of inherited metabolic disease linked to cellular metabolism of vitamin B12 : study in two murine models of invalidation of Mtr and MMACHC genes. Biochemistry, Molecular Biology. Université de Lorraine, 2019. English. NNT : 2019LORR0319. tel-02874823 HAL Id: tel-02874823 https://hal.univ-lorraine.fr/tel-02874823 Submitted on 19 Jun 2020 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. AVERTISSEMENT Ce document est le fruit d'un long travail approuvé par le jury de soutenance et mis à disposition de l'ensemble de la communauté universitaire élargie. Il est soumis à la propriété intellectuelle de l'auteur. Ceci implique une obligation de citation et de référencement lors de l’utilisation de ce document. D'autre part, toute contrefaçon, plagiat, reproduction illicite encourt une poursuite pénale. Contact : [email protected] LIENS Code de la Propriété Intellectuelle. articles L 122. 4 Code de la Propriété Intellectuelle. articles L 335.2- L 335.10 http://www.cfcopies.com/V2/leg/leg_droi.php http://www.culture.gouv.fr/culture/infos-pratiques/droits/protection.htm Ecole Doctorale BioSE (Biologie-Santé Environnement) Thèse Présentée et soutenue publiquement pour l’obtention du titre de DOCTEUR DE l’UNIVERSITE DE LORRAINE Mention : « Sciences de la Vie et de la Sante » Par Viola Jepchumba KOSGEI Manifestations cardiaques des maladies héréditaires du métabolisme cellulaire de la vitamine B12 : étude sur deux modéles murins d’invalidation des génes Mtr et MMACHC Cardiac manifestations of inherited metabolic disease linked to cellular metabolism of vitamin B12: study in two murine models of invalidation of Mtr and MMACHC genes Le 10 Décembre 2019 Membres du jury : Rapporteurs : M. Edward Valerian QUADROS : PU, Département de Médicine et Anatomie/Biologie Cellulaire Brooklyn, NY, USA M. Sébastien BLAISE : MCU, CNRS UMR/URCA 7369, Reims France Examinateurs : M. Jean-Louis GUÉANT : PU-PH, UMR 1256 INSERM, Nancy France Mme. Ebba NEXO : PU-PH, Département de Biochimie Clinique, Aarhus N, Denmark M. Yves JUILLIERE : PU-PH, CHRU Nancy Département de Cardiologie, France Mme. Rosa-Maria GUEANT-RODRIGUEZ : PU-PH, UMR 1256 INSERM, Nancy France, Directeur de thèse Invité : M. Ambrose K. KIPROP : PU, Département de Chimie et Biochimie, Moi University, Kenya UMR 1256 INSERM, Laboratoire de Nutrition, Génétique et Exposition aux Risques Environnementaux (NGERE), 9 avenue de la Forêt de Haye-Faculté́ de Médecine 54500 Vandœuvre-Lès-Nancy. DEDICATION I dedicate this Ph.D. Thesis to my beloved mother Francisca Kimoi Chepkong’a, my dear husband Jackson Yator and my dear children Alexis Jerotich and Emmanuel Kiptum. 3 ACKNOWLEDGEMENT I wish to express my sincere gratitude to Professor Jean-Louis Guéant, the director of the UMR 1256 laboratory for welcoming me to his laboratory, for financial assistance and facilitating my research work during the three years of my Ph.D. studies. His availability, expertise and scientific prowess, valuable advice, enthusiasm for research enabled me to progress and have pleasure in research. Thanks for having confidence in me and building my career as a researcher. Many thanks for your patience during the correction of the article manuscript and this thesis. I extend my heartfelt gratitude to my Ph.D. supervisor Professor Rosa-Maria Guéant-Rodriguez of University of Lorraine, for given me the opportunity to pursue my Ph.D. studies and accepting to supervise my work. Many thanks for everything Prof, I will never be able to thank you enough. Her scientific guidance and ideas, valuable advice, availability, encouragement and time that she devoted to me during the three years made me to achieve a lot during my studies. Thanks for facilitating my Ph.D. work, her energy and time she devoted in reading and correcting this thesis. Thanks for inviting me to share the precious Christmas holiday with her family and all the precious moments I spent with her outside the lab. Prof, I was lucky to be your student. I wish to express my appreciation to the members of the Jury for my Ph.D. thesis defense. My sincere gratitude goes to Professor Edward Valerian QUADROS and Dr. Sébastien BLAISE accepting to be the rapporteurs of my thesis and Professor Ebba NEXO and Professor Yves JUILLIERE for accepting to examine my work. I am deeply indebted to Professor Ambrose Kiprop the Dean of school of physical and biological sciences of Moi University for being my mentor. His advice, encouragement and facilitating my stay here in France is highly appreciated. I don’t have enough words to describe my gratitude. His hard work and enthusiasm for research always inspires me, thanks for being my mentor. I wish to deeply acknowledge the French government through the French Embassy in Kenya for having awarded me the scholarship to pursue my Ph.D. studies. The facilitation of my studies and my stay in France by Campus France is highly acknowledged. Sincere appreciation to Moi University for the facilitation and having given me the study leave. Thanks for making 4 it possible to realize my dream of obtaining a Ph.D. This will not only be important for my career development, benefit to Moi University but also to contribute to the knowledge in cardiovascular research for betterment of humanity. I would like to acknowledge our collaborators for their contribution in my Ph.D. work. Sincere acknowledgement goes to the L’institute Clinique de la Souris (ICS), Strasbourg for generating the transgenic mice. Many thanks go to Prof. L. Monassier. Sincere acknowledgement goes to the team of Nancyclotep-GIE Ingénieur d'études imagerie préclinique, Vandoeuvre Les Nancy, France, especially to Dr. Fatiha Maskali their help, patience and collaboration in this work. Sincere appreciation goes to the Inserm U1116 Défaillance cardiovasculaire aiguë et chronique lab, Vandoeuvre Les Nancy led by Professor Patrick Lacolley for his collaboration in this work and Veronique Laplace for her help. Many thanks go to all the staff of UMR 1256 laboratory for their expertise, discussion and sympathy during my thesis. I would like to pass my sincere appreciations to Sébastien Hergalent, the bioinformatic engineer in the UMR 1256 laboratory for analysis of proteomic and transcriptomic data. Thanks to his bioinformatic expertise I acquired a wealth of knowledge in omics studies My gratitude and appreciation go to Dr. J.M Alberto the chief engineer his great participation in my thesis work. His advice, availability, scientific prowess in biochemistry research and his unwavering support enable me to achieve a lot during my study. I would like to also pass my sincere appreciations to Fatiha Elkhafifi former Master II student for her contribution to towards this work. Many thanks to Remy and Veronique for training me and taking care of the mice, Dr. Céline and Dr. Carol for their contribution to this work. I would like to pass my gratitude to Dr. Natasha and Dr. Shu Fung for their availability and advice. I wish to sincerely thank Dr. Brittany Balint, her expertise in immunohistochemistry, academic advice and correction of the article manuscript, her contribution to my thesis is highly appreciated. For the administrative personnel, Aline, Dominique and Catherine your assistance is highly appreciated. To Aline, thanks to her jovial character and her motherly love I enjoyed sharing the same office with her, she even went out of her way to teach me French. I would like to pass my sincere appreciation to my friends and colleague Aline, Racha and Ziad whom I shared the same office together. I appreciate the great moments we spent together. I 5 wish to also pass my gratitude and friendship to my dear colleagues and friends in the lab Amélia, Aurélie, Céline, Attah, Justine, Jeremy, Linda, Rashka, Pauline, Djseia, Tunay, Philip and Thierry. It was a pleasure to work with you. I would like to sincerely thank the family of Monique for receiving and hosting me in her house when I first arrived in France and many invitations to their family. My appreciation goes to the family of Natalie for the holidays and invitations to your family. Thanks for being my sister here in France. I would like to pass my sincere appreciation to my friend and colleague Darlene Antoine. I highly appreciated the great moments we spent together in and outside the laboratory. Darlene many thanks for reading my thesis Manuscript. I would like to appreciate Father Daniel Muhame for his encouragement and Prayers. Thanks for being there for me big brother. I thank my entire family for the encouragement, support and the confidence they bestowed on me during my studies in France. I am indebted to my Mum for encouraging me to work hard in my studies and for everything. Many thanks to my beloved husband Jackson, and my dear children Alexis and Emmanuel for their love, patience, support, encouragement and their understanding despite my long absence from home. Thanks to my dear sisters Anita, Caro and brother Ambrose for their support, Koech and Memoi thanks so much for your love, understanding and sacrifice to take care of the kids while I was in France. 6 TABLE OF CONTENTS DEDICATION .......................................................................................................................... 3 ACKNOWLEDGEMENT ......................................................................................................
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