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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) :
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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 :
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OUI
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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.