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ED BIO SORBONNE PARIS CITE Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2017-2018 Renseignements relatifs à l’Unité de Recherche : Label et intitulé : Unité de Biologie Fonctionnelle et Adaptative (BFA). Université Paris Diderot-CNRS UMR 8251 Nom et prénom du Directeur : DUPRET Jean-Marie Téléphone : 01 57 27 82 49 Télécopie : courriel : [email protected] Renseignements relatifs à l’Equipe : Nom de l’Equipe d’Accueil : Equipe Processus Dégénératifs, Stress et Vieillissement Nom et prénom du responsable : TRICOIRE Hervé Qualité du responsable : DR2 CNRS Téléphone : 01 57 29 79 51 Télécopie : courriel : [email protected] Renseignements relatifs au sujet de thèse : Nom et prénom du Directeur de thèse (HDR) : MONNIER Véronique Qualité : MCU Téléphone : 01 57 29 79 49 Télécopie : courriel : [email protected] Titre du sujet proposé : Identification de pistes thérapeutiques dans de nouveaux modèles Drosophiles de l’ataxie de Friedreich. Identification of therapeutic strategies on new Drosophila models of Friedreich’s ataxia Département (cocher le département correspondant au sujet de thèse qui n’est pas obligatoirement le vôtre) : Biologie Cellulaire et moléculaire, Physiologie et Physiopathologie Immunologie Développement Génétique Neurobiologie et Vieillissement Infectiologie, Microbiologie Summary (5 lines maximum) : Friedreich's ataxia is caused by an expansion of GAA triplets in the first intron of the gene encoding frataxin, resulting in a decrease in gene expression. This project will use new Drosophila models to identify therapeutic strategies. The main objective will be to evaluate in vivo the effectiveness of the CRISPR / Cas9 technology in excising the GAA expansions in order to increase the level of frataxin and to obtain a phenotypic improvement. Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2017-2018 Nom, prénom du directeur de l'unité de recherche : DUPRET Jean-Marie Numéro de l'unité de recherche (et établissement de rattachement) : UMR8251 Université Paris Diderot-CNRS Nom, prénom du responsable de l'équipe d'accueil (EAD) :TRICOIRE Hervé Nom, prénom du directeur de thèse : MONNIER Véronique Titre du sujet de thèse proposé : (en anglais) Identification of therapeutic strategies on new Drosophila models of Friedreich’s ataxia Citer 5 mots clés : (key words) Friedreich’s ataxia, Drosophila, Neurodegeneration, CRISPR/Cas9, Trinucleotide repeat excision. Candidat pressenti : OUI NON Contenu scientifique du programme de la thèse (en anglais) Friedreich Ataxia (FA) is the most common inherited autosomal recessive ataxia in caucasian populations and is characterized by progressive neurodegeneration and hypertrophic cardiomyopathy. FA is caused by a GAA repeat expansion in the first intron of the gene encoding frataxin, an evolutionary conserved mitochondrial protein, which results in decreased gene expression. There is currently no efficient treatment to cure or even stop the progression of the disease. Drosophila appears as an adequate animal model to study pathogenic mechanisms involved in FA and to evaluate therapeutic interventions. The team has recently generated mutants with insertion of GAA repeat expansions in the intron of the Drosophila frataxin gene, mimicking the human situation in patients. These mutants exhibit a decreased expression of frataxin leading to reduced viability. In this project, following the completion of their phenotypic characterization, these models will be used to: 1) study physiopathological mechanisms probably involved in the disease, in particular dysregulation of lipid and iron metabolism. 2) identify and characterize therapeutic compounds. Pharmacological screening already performed in the team on RNAi based-tissue specific FA models led to the identification of several candidates that will be further validated on these new models. 3) evaluate a CRISPR/Cas9 based therapy. This will be the major aim of the PhD project. Indeed, the CRISPR/Cas9 technology recently emerged as a powerful technology for genome editing and opens new perspectives for gene therapy. In the context of FA, this technology should allow the excision of the GAA expansion in order to increase the level of frataxin. The Drosophila models will provide the opportunity to assess in vivo the effectiveness of this excision system in post-mitotic cells affected in the disease such as neurons, glial cells or cardiomyocytes, to determine if this efficacy is sufficient for phenotypic improvement, and to evaluate potential side-effects of this strategy. Indiquez les cinq meilleures publications récentes de l’équipe : 1) Palandri A, L’hôte D, Cohen-Tannoudji J, Tricoire H, Monnier V. Frataxin inactivation leads to steroid deficiency in flies and human ovarian cells. Hum Mol Genet. 2015 May 1 ;24(9):2615-26. 2) Heidari R, Monnier V, Martin E, Tricoire H. Methylene Blue Partially Rescues Heart Defects in a Drosophila Model of Huntington’s Disease. J Huntingtons Dis. 2015 ;4(2):173-86. 3) Seguin A, Monnier V, Palandri A, Bihel F, Rera M, Schmitt M, Camadro JM, Tricoire H, Lesuisse E. A Yeast/Drosophila Screen to Identify New Compounds Overcoming Frataxin Deficiency. Oxid Med Cell Longev. 2015 ;2015:565140. 4) Tricoire H, Palandri A, Bourdais A, Camadro JM, Monnier V. Methylene blue rescues heart defects in a Drosophila model of Friedreich’s ataxia. Hum Mol Genet. 2014 Feb 15 ;23(4):968-79. 5) Monnier V, Iché-Torres M, Rera M, Contremoulins V, Guichard C, Lalevée N, Tricoire H, Perrin L. dJun and Vri/dNFIL3 are major regulators of cardiac aging in Drosophila. PLoS Genet. 2012 ;8(11):e1003081.