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PropositiondesujetdethèseCNRS-L/UPD

2016-2017

Carte Morpho-Bathymétrique de la Méditerranée Orientale : lamiseà jourde la régiondubassin levantinabénéficiédesdonnéesde lacampagnebathymétriqueSHALIMARde2003menéeaveclesmoyensnavalsdel’Ifremerfrançaisetavecuneéquipefranco-libanaisedel’InstitutdePhysiqueduGlobeetduCNRSL.

Danslecadredel’accordentreleConseilNationaldelaRechercheScientifiquedelaRépubliqueLibanaise(CNRS-L)et l’Université Paris Descartes (UPD) pour le co-financement des thèses de doctorat dans des thématiquesd’intérêtcommun,deuxàquatrecontratsderecherchesdoctoralespourl’année2016-2017serontmisenplace.Ces thèses sont proposées conjointement par un laboratoire de recherche de l’UPD et un laboratoire derecherche libanaisdans lecadred’uneconventiondeco-tutelleoudeco-direction.Ainsi, leséquipessouhaitantproposerdesthèsesdedoctoratpourl’année2016-2017sontpriéesdecompléterleformulairedepropositiondesujet de thèse et de l’envoyer par courriel avant le 15 septembre 2016 à l’adresse suivante:tamara.elzein@cnrs.edu.lb.Lessujetsretenusserontdiffuséspourl’appelàcandidatureetlasélectionfinaledeslauréatsse feraparuncomitémixtedesdeux institutions. Il est ànoterque le laboratoire libanais s’engageàverserdurantles3ansdethèse3000eurosparancommecontributionàlabourseaccordéeaucandidatretenu.

Piècesàjoindre:- CVduco-directeurlibanais- CVduco-directeurfrançais

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II.FichedeRenseignementssurlelaboratoired’accueilauLiban

Universitéoucentrederecherche:UniversitéAméricaineDeBeyrouth.

Laboratoired’accueil:Diabètesetcomplicationsdiabétique-Départementd’Anatomie,deBiologieCellulaireetdePhysiologie.

NomduDirecteurdulaboratoire:AssaadA.Eid

Adresse:FacultédeMédecine,AUB,BlissStreet,11-0236,RiadEl-Solh1107-2020,BeyrouthTél./Fax/Mél:+9611350000;Ext:2781

Facultéouorganismeauquelestaffiliélelaboratoired’accueil:FacultédeMédecine,AUB.

NomduCo-Directeurdethèse:AssaadA.Eid

LeDirecteurdethèsefait-ilpartiedulaboratoired’accueil:XOui

Sinon,précisezsonrattachementetsescoordonnées:

- Principauxthèmesderecherchedel’équipeoùseraeffectuéletravaildethèse:Diabèteetcomplicationsdiabétique:complicationsnerveusesdiabétiques(neurologie),néphropathiediabétiques,cardiomyopathiesdiabétiques.

- Listedespublicationsrécentesdel’équipe(pertinentesausujetproposé):

Thesearetherecentpublicationsthatappearedin2016andrelatedtodiabetesanddiabeticcomplicationandtheroleofROSindifferenttypeofdiseases.

1- EidS,BoutaryS,BraychK, SabraR,HamdyA,MoodadS,RashidA,MassaadC,BlockK,GorinY,AbboudHE,andEidAA. Rictor/mTORC2axisRegulatesNox4MediatedPodocyteInjuryinDiabeticNephropathy.AcceptedAntioxidantsandredoxSignaling,2016.

2- Eid S, Massaad C, and Eid AA. Oxidative Stress in Diabetic Neuropathy: Strategies forTreatment.DiabetesCaseRep1:101.doi:10.4172/DCRS.10000101

3- Nassif J,AbbasiSA,NassarA,Abu-MusaAandEidAA. TheRoleofNADPH-DerivedROSProduction in the Pathogenesis of Endometriosis: A NovelMechanistic Approach. J BiolRegulHomeostAgents.30(1):31-40,2016.

4- BouhadirKH,KoubeissiA,MohsenFA,El-HarakehMD,CheaibR,YounesJ,AzziG,EidAA.NovelcarbocyclicnucleosideanalogssuppressglomerularmesangialcellsproliferationandmatrixproteinaccumulationthroughROS-dependentmechanisminthediabeticmilieu.II.Acylhydrazone-functionalizedpyrimidines.BioorgMedChemLett.1;26(3):1020-4,2016.

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Lathèsesera-t-elleeffectuéeenco-tutelleouco-direction:co-direction

III.FichedeRenseignementssurlelaboratoired’accueilàl’UPD

Laboratoired’accueil:Immunologydudiabète

NomduDirecteurdulaboratoire:MalloneRobertoetLehuenAgnessontlesCo-responsabledel'équipe

Adresse:InstitutCochin-BâtimentCassiniInsermU1016-CnrsUMR8104-UniversitéParisDescartesGroupeHospitalierCochin123boulevardPort-Royal

Codepostale-Ville:75014Paris,France

Tél./Fax/Mél:+33158412440,christian.boitard@inserm.fr

Ecoledoctoraleauquelestaffiliélelaboratoired’accueil:Ecoledoctorale«Génétique,Cellule,Immunologie,Infectiologie,Développement».

NomduDirecteurdethèse:ProfesseurChristianBoitard

LeDirecteurdethèsefait-ilpartiedulaboratoired’accueil:Oui

Sinon,précisezsonrattachementetsescoordonnées:

- Principauxthèmesderecherchedel’équipeoùseraeffectuéletravaildethèse:Diabète,auto-immunité,endocrinologie,complicationsdiabétiques.

- Listedespublicationsrécentesdel’équipe(pertinentesausujetproposé):1- LuceS,BrietC,BécourtC,LemonnierF,BoitardC.Thetargetingofβ-cellsbyTlymphocytesin

humantype1diabetes:clinicalperspectives.DiabetesObesMetab.2013,Suppl3:89-97.2- KadriN,KorposE,GuptaS,BrietC,LöfbomL,YagitaH,LehuenA,BoitardC,HolmbergD,Sorokin

L,CardellSL.CD4(+)typeIINKTcellsmediateICOSandprogrammeddeath-1-dependentregulationoftype1diabetes.JImmunol.2012,188(7):3138-49.

3- PrevotN,BrietC,LassmannH,TardivelI,RoyE,MorinJ,MakTW,TafuriA,BoitardC.AbrogationofICOS/ICOSligandcostimulationinNODmiceresultsinautoimmunedeviationtowardtheneuromuscularsystem.EurJImmunol.2010,40(8):2267-76.

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IV.SujetdethèseAfairesignerobligatoirementpartouslesco-directeurs

IV.1. Titre: Rôle d’ICOS/ICOSL dans la Physiologie et laPathophysiologieduSystèmeNerveuxPériphérique.*Lathèsefait-ellepartied’unprojetderecherchefinancéparleCNRS-L:XNon

*Lathématiquesouslaquelles’inscritlathèsefait-ellepartiedesprioritésduCNRS-Lpourl’année2016-

2017(voirAnnexe):XOuiSioui,précisez (possibilitédechoisirplusqu’une): Leprojet couvredeux thématiquesnotéescommeprioritairesauxCNRS-L:

1- MetabolicDisorders

2- NeurophysiologyandBrainResearch.

IV.2.Résumé(nepasdépasser200mots)

Diabetesisamajorpublichealthproblem.Theincidenceofdiabeteshasincreasedimmenselyin the past 10 years. This alone makes it an epidemic disease. Diabetes is associated with anumber of metabolic risk factors that contribute to a high rate of micro- and macrovascularcomplications.

Diabeticneuropathyisthemostcommoncomplicationofdiabetesworldwide,affectingupto50%ofalldiabeticpatients.Diabeticneuropathydevelopsindistinctlyinpatientswithtype1andtype 2 diabetes that are the twomain forms of diabetes. However, the exact mechanisms ofalterationthatcontributestoperipheralinjuryarenotyetdefined.ICOS,throughandbeyonditsroleonTlymphocytes,controlstissuehomeostasisinthephysiologicalstatebothatthelevelofmyelination of the peripheral nervous system and of tissue repair following an injury. Thus,understanding the pathway of alteration and the role of ICOS/ICOSL in the physiology andpathophysiologyofdisease isan importantstepforthedevelopmentsofadjuncttherapiesthatwillhelpincuringDPN.

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IV.3.Contexteetproblématique(nepasdépasser200mots)

Diabetesisamajorpublichealthproblem.Theincidenceofdiabeteshasincreasedimmenselyin the past 10 years. This alone makes it an epidemic disease. Diabetes is associated with anumber of metabolic risk factors that contribute to a high rate of micro- and macrovascularcomplications.

Diabeticneuropathyisthemostcommoncomplicationofdiabetesworldwide,affectingupto50%ofalldiabeticpatients.Diabeticneuropathydevelopsindistinctlyinpatientswithtype1andtype 2 diabetes that are the twomain forms of diabetes. However, the exact mechanisms ofalterationthatcontributestoperipheralinjuryarenotyetdefined.

Specificmechanismshavebeenhypothesizedasadditiveindiabeticneuropathy, inparticularimmunemechanismsthatareinvolvedintype2diabetesasaninflammatoryprocessandintype1 diabetes as an autoimmune disease involving the activation of antigen-specific lymphocytes.Ourhypothesis is that,withinthe frameofan innate,andpossiblyadaptive, immuneresponse,diabetes-inducedoxidativestress.TheresultingoxidativestresswillinturninduceachangeinthesignalingpathwaysinvolvingICOS/ICOSligand,leadingtoSchwanncellsinjurythustodamageintheperipheralnervoussystem.

IV.4.Descriptifdesobjectifsetdel’impact(nepasdépasser200mots)

Aim1.Toinvestigatethecellularandmolecularmechanism(s)ofICOS/ICOSLinthephysiologyand pathophysiologie of the peripheral nervous system (i.e. diabetic peripheral neuropathy orDPN).

Aim2.TodeterminetheroleofICOS/ICOSLpathwaysandtheirroleinROSproductionorthe

roleofROSproductioninICOS/ICOSLalterationinvitroandintheperipheralnervoussystemofcontrol,type1andtype2diabeticmice.

Completionofthisprojectshouldyieldcrucial findingsaboutnewpathways involvedinDPN.Understanding themechanisms leading toDPN is essential if the aboveobservations are tobetranslated to clinical therapeutic regimens aimed at restoring peripheral nervous system (PNS)integrityduringthecourseofDPN.

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IV.5.Aspectappliquéet/ouaspectinnovateur(nepasdépasser200mots)

InducibleT-cellcostimulator(ICOS)isaco-stimulatorymoleculeforTlymphocytes.ItbelongstotheCD28genefamilythatmediatecostimulatorysignalsthroughinteractionwithmembersoftheB7 familyexpressedonantigen-presentingcells (APCs)and stromal cells. In theNOD type1diabetes mouse model, which develops an autoimmune disease that is directly driven by Tlymphocytes,wehaveshownthatdeficient ICOSand ICOSLexpression inducesprotection fromdiabetes.But ICOS-/-and ICOSL-/-NODmicedevelopneuromuscularautoimmunitycharacterizedbymyositis, sensory ganglionitis and, to a lower extent, inflammatory infiltrates in the centralnervoussystem.Wehaveshown in thismodel that ICOS/ICOSLcontrolboththeactivationofTcelleffectorsandTregs.Interestingly,recentevidencehasbeenproducedindicatingthatFoxP3+Tregcellsareinvolvedinrepairfollowingmuscleinjury.

It is thus possible that ICOS, through and beyond its role on T lymphocytes, controls tissuehomeostasis in the physiological state both at the level of myelination and of tissue repairfollowinganinjury.Asextensivelyshowninmultiplesclerosismodelsinwhichinflammationplaysa key role in demyelinating lesions, including generation of free radicals as well asproinflammatorycytokines,oxidativestressandinflammationarelikelyinvolvedintheperipheralautoimmuneneuropathyseen in ICOS-/- and ICOSL-/-NODmice. If involved inmyelinprocessingand/orrepairthroughTregs,ICOS/ICOSLinteractionmayinturncreatelocalconditionsfavouringthe development of nerve autoimmunity on an autoimmune genetic background, and moregenerally the development of tissue lesions in an inflammatory environment as seen in type 2diabetes. Thus, understanding the pathway of alteration and the role of ICOS/ICOSL in thephysiologyandpathophysiologyofdiseaseisanimportantstepforthedevelopmentsofadjuncttherapiesthatwillhelpincuringDPN.

IV.6.Etatdesrecherchesdansledomaineavantlathèse(nepasdépasser200mots).

ICOS/ ICOSLarewellknownasco-stimulatorymolecules forTcellsandBcells.Theirroles inimmunology are well established. Nevertheless, no data are available about their roles inmyelinogenesisandmyelindiseasesinthePNS.WehaveshownthatICOS-/-andICOSL-/-NODmiceareprotectedfromT1D,butdevelopneuromuscularautoimmunity(laboratoireBoitard).WehavealsoidentifiedseverelocomotorandmyelindeficitsinICOSandICOS-Lknockoutmice.TheICOS-/-andICOSL-/-NODmicerepresentthefirstrelevantmousemodelofspontaneousinflammatoryneuropathy.

Further,weanalyzedthestructureofthemyelinsheathsinthesciaticnerveofICOS-/-micebyelectronmicroscopy.MyelinsheathswerenotonlythinnerinICOS-/-micecomparedtowildtype,but theycontainedseveralvoidsand interstitialmyelinwas seen (inner tongues). Furthermore,myelingenesP0andPMP22aredownregulatedby30% in ICOS-/-NODmice (Fig.10C).Myelin

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Annexe: thématiquesprioritairespourlesboursesdoctorales2016-2017

Culturalheritage- Archaeology- Protection,conservationandrestorationof

artifactsandancientmanuscripts- Archaeometry

ArabiclanguageandHistory- Arabiclinguistics,dynamism,andhistory- Cognitivelinguistics(inArabic)- HistoryofScienceinArabiccivilization- Arabizationofsoftwares

Sociologyandpoliticalscience- Migrationsociology- ConflictresolutionandPost-conflictsocieties- Genderandfeministstudies- Ethicsinmediacoverageofconflicts

(conventionalandsocialmedias)

EconomicsandFinance- Entrepreneurialuniversityandinnovation- Economyofconflictareas- Lebanonaspotentialdestinationforoffshoring- ActuarialscienceandFinancialriskmanagement- Mathematicalandcomputermodelingappliedto

financeandeconomy Environmentandnaturalresources- ValorizationofLebanesecoastalzones- Petroleumstudies- Sustainablewatermanagement- Renewableenergy- Biodiversityandspeciation-Geophysics,geology,geodesy- Mitigation&managementofnaturalrisks- Airquality- Urbanplanningintheageofclimatechange

Agricultureandfood- Challengesofagriculturalactivities- Foodsafetyandfoodindustry- Veterinarymedicine- PestandAlienspecies

Medicalsciences- AddictiveDiseases- CancerResearch- Cardiovasculardiseases- Clinicalpharmacology.Pharmacy- ClinicalImmunologyandImmunopathology- DiseasesofBonesandJoints- Endocrinology- Geriatrics- InfectiousDiseases- MedicalMicrobiology- MentalDisorders,PsychosomaticDiseases

Medicalsciences(continue)- MetabolicDisorders- MethodsofEpidemiologyandPreventive

Medicine- Psychiatry- NeurophysiologyandBrainResearch.- PublicHealthandHealthServices- RespiratoryDiseases- Ethicsinmedicineandmedicalresearch

Basicscience- Theoreticalandparticlephysics- Astrophysics- Peacefuluseofnucleartechniques- Forensicchemistry- Greenchemistry- Newfunctionalmaterials

Basicscience(continue)- Biomedicalengineering- Biochemistry- MolecularandcellularBiology- Genetics- Radiobiology