Role of Orexin/OXR system in digestive chronic inflammatory diseases

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 : Centre de Recherche sur l’inflammation (CRI)/ INSERM UMR 1149
Nom et prénom du Directeur : MONTEIRO Renato
Téléphone : 01 57 27 77 55 Télécopie : 01 57 27 74 71
Courriel: [e-mail]
Renseignements relatifs à l’Equipe :
Nom de l’Equipe d’Accueil : De l’inflammation au cancer dans les maladies digestives
Nom et prénom du responsable : PARADIS Valérie
Qualité du responsable : PUPH
Téléphone : 01 40 87 54 63 Télécopie : 01 40 87 70 00
Courriel : val[email protected]
Renseignements relatifs au sujet de thèse :
Nom et prénom du Directeur de thèse (HDR) : COUVINEAU Alain
Qualité : DR INSERM
Téléphone : 0157277488 Télécopie : 01 57 27 74 71
Courriel : [e-mail]
Titre du sujet proposé :
- Role du système Orexine/OXR dans les maladies inflammatoires chroniques digestives.
- Role of Orexin/OXR system in digestive chronic inflammatory diseases.
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) :
Orexins (OxA and OxB) are hypothalamic peptides involved in the sleep regulation for which we have demonstrated
its anti-tumoral and anti-inflammatory role in the digestive tract. In this context, the proposed project aims to study
1) the anti-inflammatory role of OxA in digestive chronic inflammation and; 2) the role of OxA in inflammation-
associated cancers. This project will offer to determine the impact of orexin in the immune cells in inflammatory and
inflammatory-associated cancer context and to determine the signaling pathways involved in these effects

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 : MONTEIRO Renato
Numéro de l'unité de recherche (et établissement de rattachement) : UMR 1149, Paris 7
Nom, prénom du responsable de l'équipe d'accueil (EAD) : PARADIS Valérie
Nom, prénom du directeur de thèse : COUVINEAU Alain
Titre du sujet de thèse proposé :
- Role of Orexin/OXR system in digestive chronic inflammatory diseases.
Citer 5 mots clés : GPCR, Orexin, Inflammation, Cancer, Signalling pathway
Candidat pressenti :  OUI  NON
Contenu scientifique du programme de la thèse (en anglais)
Our group which has an international expertise in the neuropeptide receptors field, has identified the anti-tumoral
and anti-inflammatory roles of orexins and their receptors in digestive tract. Orexins (OxA and OxB) are
hypothalamic peptides involved in the sleep regulation. Orexins mediate their central and peripheral biological effects
by binding to two GPCR subtypes, OX1R and OX2R, leading to the subsequent release of intracellular calcium
transients via a Gq-dependent pathway. In the last few years, we have identified a new paradigm of orexin receptor
signaling pathway demonstrating that its activation induced a mitochondrial apoptosis independent of intracellular
Ca2+ production, in digestive cancer cells (colon, pancreas and liver). Considering that intestinal bowel diseases (IBD)
and pancreatitis displayed a high risk to develop a cancer, we have found a strong expression of OX1R in IBD
including Crohn’s disease and ulcerative colitis (UC). We have studied the role of OX1R/OxA in UC by using two
murine models including classical DSS model and a genetically modified model consisting of a double KO of IL-10
and NOX-1 which spontaneously develop UC. Our data revealed that ip injections of OxA: 1) strongly improved UC
symptoms; 2) inhibited the production of pro-inflammatory cytokines secreted by immune cells and; 3) inhibited the
NFκB activation and eIF2α phosphorylation, leading to epithelial cell protection. In this context, the proposed thesis
project aims to study 1) the anti-inflammatory role of OxA in digestive chronic inflammation and; 2) the role of OxA
in inflammation-associated cancers. This project will propose to 1) determine the expression of OXR in immune cells
(PBMC, intra-tissues…); 2) determine the impact of orexin in the immune cells in inflammatory context; 3) identify
which immune cell lineage is involved in this response; 4) determine the signaling pathway involved in anti-
inflammatory effect of orexin and; 5) investigate the impact of orexin in inflammation-associated cancers mouse
model and to study the role of immune system in this process. The technical procedure will use Cell Biology (immune
cells purification, FACS, cell culture, Ca2+ determination, Immunolabeling…), Biochemistry (WB, apoptosis…),
Pharmacology (inhibitors use, development of therapeutical molecules…), Molecular Biology (reporter gene vectors,
BRET vectors…), Animal Experimention and Animal Imagery (MRI, echo doppler…). This project should allow us
to understand the anti-inflammatory role of orexins and participate in the development of molecules for therapeutic
use.
Indiquez les cinq meilleures publications récentes de l’équipe :
 Speisky D, Couvelard A, Moreau S, Dubois N, Rebours V, Sauvanet A, Bedossa P, Paradis V, Ruszniewski P,
Couvineau A, Voisin T Orexin receptor, OX1R, in pancreatic cancer: a new proapoptotic target FASEB J 2017
(in revision)
 Blais A, Drouin G, Chaumontet C, Voisin T, Couvelard A, Even PC, Couvineau A. Impact of Orexin-A Treatment
on Food Intake, Energy Metabolism and Body Weight in Mice. PLoS One. 2017 12:e0169908.
 Nicole P, Couvineau P, Voisin T and Couvineau A Crucial role of the orexin-B C-terminus in the induction of
OX1R-mediated apoptosis: analysis by alanine-scanning, molecular modeling and site-directed mutagenesis.
British J. Pharmacol 2015 172:5211
 Alexandre D, Hautot C, Mehio M, Jeandel L, Courel M, Voisin T, Couvineau A, Gobet F, Leprince J, Pfister C,
Anouar Y, Chartrel N. The orexin type 1 receptor is overexpressed in advanced prostate cancer with a
neuroendocrine differentiation, and mediates apoptosis. Eur J Cancer. 2014:2126-33.
 Voisin T, El Firar A, Fasseu M, Rouyer-Fessard C, Descatoire V, Walker F, Paradis V, Bedossa P, Henin D, Lehy
T, Laburthe M. Aberrant expression of OX1 receptors for orexins in colon cancers and liver metastases: an
openable gate to apoptosis. Cancer Res. 2011; 71:3341-51.