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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 : Institut Cochin Nom et prénom du Directeur : Pierre-Olivier Couraud Téléphone : 0140516457 Télécopie : 01 40 51 64 73 Courriel: [email protected] Renseignements relatifs à l’Equipe : Nom de l’Equipe d’Accueil : Dynamique des interactions lymphocytaires T Noms et prénoms des responsables : Emmanuel Donnadieu et Clotilde Randriamampita Qualités des responsables : DR2 CNRS et CR1 CNRS Téléphone : 0140516560 Télécopie : 01 40 51 65 55 Courriel : [email protected] et [email protected] Renseignements relatifs au sujet de thèse : Nom et prénom du Directeur de thèse (HDR) : Jérôme Delon Qualité : CR1 Inserm Téléphone : 01 40 51 66 40 Télécopie : 01 40 51 65 55 Courriel : [email protected] Titre du sujet proposé : (En français) Caractérisation génétique et immunologique d’un syndrome auto-inflammatoire atypique (associant un psoriasis et un déficit immunitaire) résultant d’une mutation dans le gène codant la RhoGTPases Cdc42 (En anglais) Genetic and immunological characterization of an atypical autoimmune syndrome (associated with psoriasis and immune deficiency) resulting from a mutation in the gene encoding the RhoGTPase Cdc42 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) : The auto-inflammatory diseases such as psoriasis are due to mutations of genes involved in the regulation of immunity. Dr Asma Smahi's group has recently identified a mutation in the Rho GTPase Cdc42 in a patient with a severe form called "Generalized Pustular Psoriasis" (GPP). The purpose of this PhD collaborative project is to elucidate the functional consequences of the mutation in Cdc42 as a cause and therapeutic target for the GPP syndrome Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2017-2087 (L’ensemble de cette fiche ne doit pas dépasser 1 page) Nom, prénom du directeur de l'unité de recherche : Pierre-Olivier Couraud Numéro de l'unité de recherche (et établissement de rattachement) : Inserm U1016, Institut Cochin Noms, prénoms des responsables de l'équipe d'accueil (EAD) : E. Donnadieu et C. Randriamampita Nom, prénom du directeur de thèse : Jérôme Delon Titre du sujet de thèse proposé : Study of a Cdc42 mutation in a patient with a Generalised Pustular Psoriasis syndrome (en anglais) Citer 5 mots clés : auto-inflammatory diseases, Cdc42, T lymphocyte, subcellular localisation, signalling (key words) Candidat pressenti : OUI NON Contenu scientifique du programme de la thèse (en anglais) Auto-inflammatory diseases (AIDs) are due to mutations in genes involved in the regulation of immunity. The group of Asma Smahi has, for the first time, determined the genetics of a severe form of psoriasis, the Pustular Generalized Psoriasis (PPG). It results from loss-of-function mutations of the IL36RN gene which encodes the IL-36Ra antagonist, a NF-kB-mediated negative regulator mediated by the inflammatory cytokine IL-36. This study allowed the identification of pathophysiological mechanisms of the most common form of psoriasis, plaque psoriasis that affects 4.6% of the population in developed countries. More recently, a patient with a more atypical PPG syndrome was diagnosed. Upon sequencing his exome, a mutation was found in the Cdc42 gene. Cdc42 is a small ubiquitous G protein belonging to the Rho GTPases family. Cdc42 has multiple roles during development and adulthood in both immune and non immune tissues. It controls cellular polarity, migration, adhesion and cell proliferation. The first objective of this project is to study the impact of the identified mutation on the localization and function of the Cdc42 protein. Preliminary data using a construct encoding GFP-Cdc42 and exhibiting the mutation indicate that mutated Cdc42 appears to be trapped in the Golgi apparatus both in a T lymphocyte and endothelial cell lines. We now wish to understand, at the molecular level, how this mutation can affect the localization of the mutated protein (lack of interaction with known partners? Increase anchoring to the Golgi membranes?) and determine to what extent this subcellular localization defect affects the functionality of the protein. We will also seek to correct this defect in localization of the mutated protein in vitro. We have cells from the patient in which we will analyze the subcellular localization of Cdc42, attempt to correct it and analyze the impact of the Cdc42 mutation on the function of these cells. Altogether, this project will enable us to study more precisely the regulation of intracellular trafficking of Cdc42 and to possibly offer a therapeutic cure for this patient. Indiquez les cinq meilleures publications récentes de l’équipe : - Bal E, Laplantine E, Hamel Y, Dubosclard V, Boisson B, Pesacatore A, Picard C, Hadj-Rabia S, Royer G, Steffann J, Bonnefont JP, Ursini VM, Vabres P, Munnich A, Casanova JL, Bodemer C, Weil R, Agou F, Smahi A.Lack of interaction between between NEMO and SHARPIN impairs linear ubiquitination and NF-κB activation, and leads to incontinentia pigmenti. J Allergy Clin Immunol. 2017 Feb - Megrelis L, Delon J. Rapid and robust analysis of cellular and molecular polarization induced by chemokine signaling. J Vis Exp (2014) (9 - Rougerie P, Largeteau Q, Megrelis L, Carrette F, Lejeune T, Toffali L, Rossi B, Zeghouf M, Cherfils J, Constantin G, Laudanna C, Bismuth G, Mangeney M, Delon J. Fam65b is a new transcriptional target of FOXO1 that regulates RhoA signaling for T lymphocyte migration. J Immunol. (2013) 190(2):748-55. - Rougerie P, Delon J. Rho GTPases: masters of T lymphocyte migration and activation. Immunol Lett. (2012) 142(1-2):1-13. - Marrakchi S … Smahi A. interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med. 2012 Aug 18;365(7):620-8.