MARIESKLODOWSKA-CURIEACTIONS
Co-fundingofregional,nationalandinternationalprogrammes(COFUND)
DOC2AMUPROJECT2017CALLFORAPPLICATIONS
HYPERSECRETIONINSEVEREAIRWAYDISEASES:ANINTEGRATEDBIOPHYSICAL
APPROACHOFTHEMUCOCILIARYASPECTOFTHEBRONCHIALEPITHELIUM
1.DESCRIPTIONOFTHEPHDTHESISPROJECT
1.1OBJECTIVESOFTHEPROJECTBASEDONTHECURRENTSTATEOFTHEART
Severechronicrespiratorydiseasesaffecthundredsofmillionsofpeopleworldwide.Theyareassociatedwith
an impaired mucociliary clearance, which results in a sharp increase in susceptibility to infections and
inflammation. Mucociliary clearance is an essential innate mechanism consisting of the transport, at the
surface of bronchial epithelium, of a protective sticky and viscoelastic fluid called mucus. External inhaled
pathogensandparticlestrappedinthemucusareeliminatedfromtheairwaysviaanactivetransport,which
relies on the continuous beating of microscopic cilia located on ciliated epithelial cells. The identification of
specific biological pathways involved in the deleterious changes of the mucociliary system allows a better
understanding of the abnormal mucociliary clearance. Yet, mucociliary transport relies on physical
mechanisms,whichinvolveactivecilia-generatedforces,hydrodynamiccouplingbetweentheciliarybeatsand
theviscoelasticresponseofmucus.Itisthereforecrucialtoelucidatethesemechanisms.
Epitheliumsurface.Thephysicalsystem
The mucociliary system is schematized in Fig. 1. Mucus, secreted at the airway surface is organized in two
layers. The top one is made of a shear-thinning gel,
which is transported out of the respiratory tract to
eliminate inhaled pollutants. The bottom periciliary
layerisincontactwiththeepithelialcells.Itconsists
inapolymerbrush,composedofmucinstetheredto
cilia. Macroscopic transport of mucus is induced by
the hydrodynamic force resulting from the collective
andcoordinatedmotionofcilia.
Fig.1Schematicrepresentationofthetwolayersmucociliarysystem
Fluidtransportandciliaryactivityonreconstitutedinvitrohumanepithelia
Few experimental studies have been dedicated to the physics of the mucociliary system because of the
difficulty to perform in-vivo studies. The recent development of primary airway epithelial cells culture at Air
LiquidInterface(ALI)bytheteamofthethesisco-directorallowsovercomingpreviouslimitations.Thisin-vitro
culture model mimics the mucus-secretory and ciliated surface phenotype expressed in-vivo. It has been
reported that the mucus could be circularly transported as a rigid disk over a whole culture chamber. In the
team of the thesis director, it was very recently showed that local circular flow patterns also spontaneously
arise during ciliogenesis and the size of these patterns scales with the surface density of beating cilia (paper
submitted). ALI reconstituted epithelia from severe asthma patients were shown to be unable to generate
macroscopic mucus flow, due to an abnormal low ciliary density. Furthermore, a fine regulation of the local
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densityofbeatingciliaandofthedirectionalcoordinationofciliarybeatswasdiscoveredwithinthesecircular
flowdomains.Bothquantitiesprogressivelyincreasedwiththedistancetotheflowdomaincentre,suggesting
thathydrodynamicforcescouldaffectciliarybeatdirectionsandciliarydensity.Yet,thecouplingbetweenthe
ciliaandthemucusaswellasthedynamicsandcoordinationoftheciliaremainpoorlyunderstood.
Physicalphenomena
Thefirstobjectiveoftheprojectistounderstandthephysicalmechanismsunderlyingthemucustransportata
macroscopicscale.Thesystemsisactive,nonlinearandcoupledsystem.Indeed,thebeatofanindividualcilium
generatesalocalflow,inbothtopandpericiliaryfluids,whichexertsahydrodynamicforceondistantcilia.This
force perturbs their beating motion (direction, phase...), which in turn alters the flow. These hydrodynamic
interactionsamongciliadependoninter-ciliadistances,beatpatternsandmucusrheologicalresponse.
Acriticalissueistounderstandhowcilium-ciliumhydrodynamicinteractionsaffecttheiractivityandwhether
theyareinvolvedinthecoordinationofthemotionofdistantcilia.Mechanosensingisalsoacandidateforcilia
coordination.Indeed,thehydrodynamicforceexertedandsensedoneachciliumofagivenciliatedcellmight
be transduced into a biochemical signal activating the ciliated cell. Cells could then be able to regulate the
metabolismofciliaryactivity(changingbeatfrequency)orinducetransdifferentiationofadjacentcells(e.g.to
newciliatedcells).Thesecondobjectiveoftheprojectistoquantitativelydescribetherelationbetweenciliary
activity,mucusrheologicalpropertiesandmucustransport.Thegoalistoprovideaquantitativeframeworkto
interpretabnormalmucociliarytransportfromtheobservationofmorphologicalandfunctionaldefectsofthe
bronchialepitheliuminchronicrespiratorydiseases.
Nanohealthaxis:Biologicalmonitoringischallenginginthecaseofnanoparticlesexposure,andabottleneck
is to understand inhaled dose and deposition. The deposition of nanoparticles in airways is an important
mechanism behind chronic airway diseases exacerbations and development, that is the reason why nanoparticle effects and deposition in epithelial cultures obtained from healthy, smokers and subjects with
variouschronicairwaydiseaseswillbestudiedinthepresentproposallinkingthistonanohealth.
Thegoaloftheproposedprojectistoinvestigatetheintricateinterplaybetweenthecollectivedynamicsofthe
ciliaandthetransportofmucus,whichresultsintheformationofpatternsatthemicro/macroscopicscale.We
wanttoidentifytheabnormalphysicalpropertiescharacteristicofthemucociliarytransportinthecontextof
severeasthma.
1.2METHODOLOGY
Experimentalresearch
Here we propose a quantitative experimental study to address the question of the coupling between the
mucustransportandtheciliaryactivity.Ourmultidisciplinaryapproachwillbebasedonalargepanelofhuman
bronchial ALI cultures of control subjects and patients with severe asthma, pieces of tracheas provided by
surgeons,coupledwithrheometry,advancedopticalmicroscopytechniquesandimageprocessing.
- BronchialALIculturesofvariousgeometriesobtainedfromendobronchialbiopsieswillbepreparedinthelab
oftheco-directorP.Chanez.Thematurationofthereconstitutedepitheliumandtheemergenceofsurface
mucusflowduringciliogenesiswillbemonitored.
- Rheological properties of the mucus secreted in the various ALI cultures will be studied in a dedicated
rheometerincollaborationwithDr.Favier(LaboratoireM2P2,Marseille).
- The ciliary activity will be assessed in the lab of the thesis director using optical microscopy on living ALI
cultures. Confocal microscopy will be performed to image beating and immobile cilia. DIC optical
microscopy will be used to study ciliary beat synchronization. Bright field microscopy coupled with image
processingwillallowmeasuringciliarydensity,beatdirectionandfrequency.Epitheliummorphologywillbe
studiedwithimmunohistochemistryandimmunofluorescence
- SurfaceandpericiliaryflowswillbedeterminedbyParticleImageVelocimetry(PIV)performedandprocessed
inthelabofthethesisdirectorinCINaM.
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-
Methodologyorprocessused
TheproposedapproachissummedupinFig.2.Wewillstudysurfaceflowandmucustransportbytuningthree
parameters acting on hydrodynamic interactions: the ciliary activity, the surface and periciliary rheological
properties and the boundary conditions. We will quantify the interplay between the ciliary activity and the
spatio-temporalevolutionofmucustransport.
We will study ciliary activity as a function of the
severity of the respiratory disease and of the
phenotypeofthepatientstoestablishan“ID”card
of patients which links the phenotype to ciliary
activityandmucustransport.
The coupled feedback of hydrodynamics on ciliary
activity will be studied during ciliogenesis. We will
expose several ALI cultures at an early stage to
different hydrodynamic conditions and compare
thetemporalevolutionoftheirciliaryactivity.This
willallowustocharacterisetheroleofthemucus
and its rheological properties on ciliary activity,
thusonmucustransport.
Fig.2Schematicoftheinterplaybetweenactiveciliaandmucustransport-Thecouplinginthemucociliary
system arises from the hydrodynamic interactions. The tunable parameters are the cilium activity, the
boundary conditions of the culture chamber and the rheological properties of the periciliary and surface
fluids. The possible role of mechanotransduction mechanisms on the coordination/synchronisation of the
ciliawillbetestedbyapplyinganexternalhydrodynamicforce.
1.3WORKPLAN
Gantt
Chart
Webrieflydetailthedifferenttasks
ALI Culture – Samples of various diameters (12 or 24mm) and geometries (linear channel or ring) with wellth
characterized phenotypes will be prepared an used at day 14 (cilia apparition) and studied until day 35th.
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TheseALIculturesareroutinelyusedinP.Chanez’slab.Thesecretedmucuswillbeperiodicallycollectedatthe
surfaceoftheculturesanditsrheologicalpropertiesdeterminedinacone-platerheometer.
Surfaceflowpatternsandmucustransport–Size,directionandvelocityofbothsurfaceandpericiliaryfluids
will be quantified on each culture chamber, and local flow patterns characterised. Experiments will be also
doneonpiecesofepitheliumpeeledfrompiecesoftracheaprovidedbysurgeons.Forthatpurposewewilluse
fluorescent nanobeads (that enter into the periciliary layer) and microbeads on the surface fluid and track
them. We will determine whether the presence of local circular surface-flow domains reported in circular
chambersisanintrinsichydrodynamicphenomenonorisdrivenbythegeometryoftheepithelialculture.The
surfacefluidrheologywillbevariedbydilutingnativemucus,orbyreplacingitbyaNewtonianfluidoragel
(agarose).
Ciliaryactivity–Thetemporalevolutionoftheciliaryactivityoneachflowdomainwillbefollowed(fromday
th
th
14 today35 )underdifferenthydrodynamicconditionsbyvaryingtherheologicalpropertiesofthesurface
fluid or by applying controlled external surface flows at the epithelium surface. The temporal evolution of
ciliarydensity,ofphases,directionsandfrequenciescoordinationofciliarybeats,andoftheflowdomainsize
will be measured. The challenge will be to implement innovative image processing algorithms that we can
automaticallyapplied.
1.4 SUPERVISORSANDRESEARCHGROUPSDESCRIPTION
Thisprojectispartofanintegrativeapproach,supportedbytheFrenchNationalAgencyforResearch,which
involves physicians, biologists and physicists from Marseille and Montpellier to study the dysfunction of the
bronchialepitheliuminthecontextofchronicrespiratorydiseases andwhichwillendattheendof2017.The
projectpresentedhereisbasedonthediscoveryduringtheANRofanoriginalcouplingbetweenciliaryactivity
and mucociliary transport, suggesting the existence of unexplained mechanotransduction effects (currently
being published). These behaviors need to be detailed, quantitatively described, understood and valued in a
clinicalsetting.Thisistheobjectiveofthisproject.AfirstCofund'prestige’fundinghasjustbeenobtainedto
hireapostdocin2017todevelopnewobservationtoolsandtostartafirstmeasurementcampaign.
Thestrongadvantageofourprojectreliesonitsmultidisciplinaryandontheavailabilityofhumansampleswith
well-characterizedclinicalphenotypesthankstothecollaborationoftherenownedteamofphysiciansledbyP.
ChanezinthefieldofchronicrespiratorydiseaseswiththegroupofphysicistsledbyA.Viallat.
The research group of Annie Viallat belongs to the new Departement ‘Physics and micro-nanoEngineering of
livingsystems’inCINaM.Itisaveryactivepartner,hasfacilitiesforcellcultureandhasexcellentequipmentfor
light microscopy and Velocimetry measurements. The group has great expertise in biophysics, soft matter
physics,andphysicsofactivematter.Thegrouphasrecentlyhighlightednoveleffectsonthecouplingbetween
ciliaryactivityandmucustransportinchronicrespiratorydiseases.
TheresearchgroupofPascalChanez
PascalChanezandhisgroupisinvolvedinchronicairwaydiseasesmanagement.Initiallytheirworkfocusedon
airway inflammation and steroid sensitivity (Bousquet et al. NEJM 1990, Chanez et al. AJRCCM 1999) before
studying evidences for delayed or defective resolution of inflammation as hallmarking asthma and COPD
(Bonnans et al AJRCCM 2002, Vachier et al AJRCCM 1999, Chavis et al J Exp Med 1997). They developed airliquid interface cultures of airway epithelium from endobronchial biopsies allowing identification of
characteristic epithelial phenotypic changes (Bourdin JACI 2007, Gras et al JACI 2012, Pharmacol &
Therapeutics 2013, Gamez Chest 2014, Science 2015). Thorough clinical investigations are now ongoing for
therapeuticinnovations(MagnussenNEJM2014,PavordNEJMetLancet2012,OrtegaNEJM2014,Brightling
LancetRespirMed2015).
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2.3IDIMENSIONSANDOTHERASPECTSOFTHEPROJECT
2.1 INTERDISCIPLINARYDIMENSION
The project draws its originality from the integrated translational approach ‘from bench to bedside’ and is
interdisciplinary by essence. The group led by A.Viallat combines the expertise on soft matter and complex
fluids,fluiddynamicsandbiomechanicsandwillbeinchargetosupervisebiophysicsanalysis(ciliaryactivity,
mucustransport).ThegroupledbyP.Chanezmastersamodelofinvitroand3-dimensionalreconstructionof
the bronchial epithelium as seen in human airways. Moreover, the recruitment of asthmatic subjects in
Hospitaldepartmentisresponsibleforalargenumberofbronchialendoscopicspecimensmakingitpossibleto
carryoutcomparativestudiesbetweenhealthyandpathologicalcells.P.Chanezwillsupervisetherecruitment
ofpatientsandproductionofinvitroreconstitutedepithelium.
2.2INTERSECTORALDIMENSION:
Our department, at APHM managed by Dr Laurie Pahus (PharmD) participates in more than 30 clinical trials
with industrial or academic sponsors. Our main activity focuses on severe asthma, COPD and idiopathic
pulmonary fibrosis. About 100 patients are monitored monthly. Many unmet needs exist for the therapeutic
management of these chronic respiratory diseases. In order to identify new targets for future innovative
treatmentsandmorepowerfuldiagnosistools,bothfundamentalandclinicalresearchesareneeded.Thereby,
we develop several translational research projects. The success of this project depends on the access to the
largest number of human bronchial epithelium samples and sputum samples. These samples are collected in
ourdepartmentonclinicalresearchparticipantsaftertheirappropriateconsent.Wehavetheabilitytocollect
adequatebiologicalsamplesusingforexamplebronchialendoscopyorinducedsputumtechniques.
2.2 INTERNATIONALDIMENSION:
The student will participate to several international conferences on the subject. He will participate to the
Gordon Research conference on Cilia, Mucus and Mucociliary interactions held every two years and to the
annualconferenceoftheAmericanPhysicalSociety,divisionofFluidMechanics.
ThestudentwillbewelcomeinvariouslaboratorieswithinEuropeincludingDrCharlesPiletteinBelgiumand
DrJamilaChakirinQuebec.Intheselaboratories,hewilllearnsomenewtechniquesrelatedtohisprojecton
epitheliumdevelopedinourLaboratory.
3.RECENTPUBLICATIONS
Ciliaryactivity:
M-K.Khelloufi,D.Gras,D.Garulli,A.Viallat,P.Chanez,Analysisofciliarybeatinginreconstitutedbronchial
epitheliumfromchronicairwaydiseases,,EuropeanRespiratoryJournal,42,3185,2013(abstract)
DuboisAV,MidouxP,GrasD,Si-TaharM,BréaD,AttucciS,KhelloufiMK,RamphalR,DiotP,GauthierF,Hervé
V.Poly-L-LysinecompactsDNA,killsbacteria,andimprovesproteaseinhibitionincysticfibrosissputum.AmJ
RespirCritCareMed.2013Sep15;188(6):703-9.
Epitheliummodel
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Gras D, Martinez-Anton A, Bourdin A, Garulli C, de Senneville L, Vachier I, Vitte J and Chanez P. Human
bronchialepitheliumorchestratesdendriticcellactivationinsevereasthma.EurRespJ.2017Inpress.
CarliniF,PicardC,GarulliC,PiquemalD,RoubertouxP,ChiaroniJ,ChanezP,GrasD*,DiCristofaroJ*.Bronchial
epithelialcellsfromasthmaticpatientsdisplaylessfunctionalHLA-Gisoformexpression.FrontiersinImmunol.
2017Inpress(*co-dernierauteur)
SchuijsMJ*,WillartMA*,VergoteK,GrasD,DeswarteK,EgeMJ,MadeiraFB,BeyaertR,vanLooG,BracherF,
vonMutiusE,ChanezP,LambrechtBN,HammadH.Farmdustandendotoxinprotectagainstallergythrough
A20inductioninlungepithelialcells.Science.2015Sep4;349(6252):1106-10.
GrasD,BourdinA,VachierI,deSennevilleL,BonnansC,ChanezP.Anexvivomodelofsevereasthmausing
reconstitutedhumanbronchialepithelium.JAllergyClinImmunol.2012May;129(5):1259-1266.
Severeasthma(2016)
PretolaniM,BergqvistA,ThabutG,DombretMC,KnappD,HamidiF,AlavoineL,TailléC,ChanezP,ErjefältJS,
Aubier M. Effectiveness of bronchial thermoplasty in patients with severe refractory asthma: clinical and
histopathologicalcorrelations.JAllergyClinImmunol.2016Sep5.
GrasD,Chanez P.Newsociologyforbetterunderstandingsevereeosinophilicasthma:introducingtheSOCS
family.EurRespirJ.2016Sep;48(3):608-10.
Kuo CS, Pavlidis S, Loza M, Baribaud F, Rowe A, Pandis I, Hoda U, Rossios C, Sousa A, Wilson SJ, Howarth P,
DahlenB,DahlenSE,ChanezP,ShawD,KrugN,SandströmT,DeMeulderB,LefaudeuxD,FowlerS,FlemingL,
Corfield J, Auffray C, Sterk PJ, Djukanovic R, Guo Y, Adcock IM, Chung KF; U-BIOPRED Project Team. A
Transcriptome-drivenAnalysisofEpithelialBrushingsandBronchialBiopsiestoDefineAsthmaPhenotypesin
U-BIOPRED.AmJRespirCritCareMed.2016Aug31.
BarnigC,VeaudorM,GautierC,Margelidon-CozzolinoV,PigeariasB,DevouassouxG,RaherisonC,DeBlayF,
Chanez P.[Howtoconsidertriggersandcomorbidconditionsinsevereasthmainadults].Presse Med. 2016
Aug18.
CaillaudD,ChanezP,EscamillaR,BurgelPR,Court-FortuneI,Nesme-MeyerP,DesleeG,PerezT,PaillasseurJL,
Pinet C, Jebrak G, Roche. Asthma-COPD overlap syndrome (acos) versus "pure" copd: a distinct phenotype?
N.Allergy.2016Aug9.
4.EXPECTEDPROFILEOFTHECANDIDATE
Thecandidatewillhaveasolidbackgroundinexperimentalphysicsandapassionforpluridisciplinarity.Hewill
haveastronginterestforactivematter,softmatter,biologyandmedicine.Hewillhaveanacademic
backgroundofphysicsand/ormedicine.Hewillhaveexperimentalskillsonopticalmicroscopy.Skillsonimage
analysis,dataprocessingwillbeappreciated.TheknowledgeofImageJ,matlab,orlangageofprogrammation
likepythonwillbeuseful.
Thecandidatemustbesociable,liketodiscussandmaketheinterfacebetweendifferentandcomplementary
scientificcultures.Onadailybasis,hewillhavetointeractwithphysicists,biophysicists,biologistsanddoctors.
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5.SUPERVISORS’PROFILES
AnnieViallat’sprofile
Biography:
Annie Viallat is engineer of Ecole Polytechnique (Paris, France). She received her PhD in Physics from the
University of Grenoble (France) in 1987, working on polymer gels and NMR. After a postdoc on theory of
conjugatedpolymersintheMaterialsDepartments(UCSantaBarbara),shejoinedtheSpectrométriePhysique
lab (Grenoble) in 1989, studying polymer gels and heterogeneous polymer solutions. Her research moved to
biologicalphysicsin1999.From2005to2015sheledagroupinMarseilleonthedynamicsinmicroflowsof
vesiclesandbloodcells.Since2016,sheistheheadofdepartment‘PhysicsandEngineeringforLivingMatter’
inCINaM(Marseille),workingonactivematter,microcirculationofredbloodcellsindiseaseandphysicsofthe
mucociliaryclearance.
Positions:
2016-HeadofdepartmentatCINaMActiveMatter,biologicalphysics,biologicalfluids,
2007-2014DirectoroftheCNRSFrenchConsortium‘PhysicsfromCelltoTissue’
2005-2015Groupleader‘biomimetics’,Adhesion&Inflammationlab.,MarseilleBiophysics-Biomechanics
1999-2002GroupLeader,LaboratoireSpectrométriePhysique,Grenoble,Polymers,GiantLipidvesicles
1989-1999JuniorResearchScientist,LaboratoireSpectrométriePhysique,Grenoble
Cursus
1982IngénieurEcolePolytechnique,Paris
1984Ing.Génierural,EauxetForêts,Paris
1984DEAPhysiquedusolide,Paris7
1987Doctoratdephysique,1987,UniversitédeGrenoble
1994HDR,Grenoble
Currentresearcharea:ActiveMatter-BiofluidPhysics–CellRheology–Fluidandelasticityinlivingsystems:
-Softmicro-shells,artificialcapsules,liposomes,encapsulation.
-Redbloodcellsdynamicsinflow:Liftforce–CellBiomechanics–Sedimentation–fluidstructureinteraction
-Bloodcelldynamicsinthemicrovasculature:Microfluidics-redbloodcellsinsubmicronsplenicslits-
vasoocclusioninsicklecellanemia,bloodcellsadhesionandmargination
-Physicsofthemucociliarytransport:collectivebehaviourofbronchialcilia,flowpatterns,couplingbetween
ciliaryactivityandmucustransport
Relevantthesissupervisionhistorysince2000.Durationofthesis3yearsexceptforZHHuangandKKhelloufi
(4years)
2002:UJFM.Abkarian,CRCNRS,médailledebronze,publications:1PRE,2Phys.Rev.Lett,2Biophys.J,2soft
Matter,
2005:UJFJ.Dalous,Researcherandnowphysician,publications:1Biophys.J
2006:UJFM.FaivreCRCNRS;publications:1PRL,1Phys.Rev.Lett.,1Prog.inColloidandPolymerSci.
2007:UJFC.VezyM.deConf.Univ.Troyes,publications:1SoftMatter
2007:UJFC.CampilloM.deConf.Univ.Evry,publications:1Prog.inColloidandPolymerSci.,1SoftMatter,1
EurophysicsLetters
2008:U.Méditerranée,ZHHuangbacktoTaiwan,publications:1SoftMatter,1NewJ.ofPhysics
2012:AMU,J.DupireIngénieurMicrofactoy(startupParis),publications:1Phys.Rev.Lett.,1PNAS,1Soft
Matter+1soumis
2015:Univ.SalvadordeBahiaLJBonfim,enseignantuniversityBrasil,publications:1PlosOne,
2015:AMUK.KhelloufiIngénieurPlatod(StartupParis),publications:1EuropeanRespiratoryJ.(proceeding),
eLifesubmitted,otherpublicationinpreparation
Nothesiscurrentlysupervised.
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PascalChanez’sprofile
Biography
Dr Pascal Chanez MD, PhD, FERS is a consultant and full Professor of Respiratory Medicine attending the
«Clinique des bronches, de l’allergie et du sommeil et de la plateforme ambulatoire du pôle thorax» at the
APHM and Aix Marseille University at Marseille France. He coordinates a research group at INSERM-CNRS
U1067inthesameinstituteontheroleofbronchialepitheliumininflammationandenvironmentalaggression
inseverebronchialdiseases.Heistheheadofaclinicalresearchgroupinvestigatingnewinnovativetreatments
forsevereasthmaandCOPD.HegainedhisMDandPhDdegreesfromtheUniversityofMontpellierandwasa
fellowattheImperialCollegeinLondonUKwithPrPJBarnes.Heistheauthorsorco-authorofmorethan300
peerreviewedarticles,reviewsandmonographs(H-index(WebofScience):60:seepubmedn=388)Heisan
editor of the European Respiratory Journal and Journal of allergy and clinical Immunology . His clinical and
researchinterestsaredevotedtoabetterunderstandingofthemechanismsofsevereasthmaandCOPDwitha
specialeffortputintobringingclinicalandbiologicalfindingstogethertoprovidetothepatientsnewspecific
biomarkers and therapies. He has demonstrated in the past his willingness and ability to gather researchers
andclinicianstogethertodecipherthecomplexityofsevereasthmainFranceandEurope.
Cursus
2008-2016:DepartmentofPulmonology,Head,APHMAixMarseilleUniversityGroupLeaderINSERMU1067
2015:Professorofmedicine"classeexceptionnelle"AixMarseilleUniversity
rst
2010:Professorofmedicine"1 "AixMarseilleUniversity
nd"
2008:Full ProfessorofmedicinePU"2 AixMarseilleUniversity
1988-2007:AttendingphysicianPHCHUMontpellier
1983-1988MedicalresidencyCHUMontpellier
1987:ResearchfellowImperialCollegeLondonUK
1977-1983:MedicalStudentCHUMontpellier
Diploma
1994PhDUniversityofMontpellier,
1994HDRUniversityofMontpellier
1988SpecialistinPneumologyUniversityofMontpellier
1988MDUniversityofMontpellier
Grants
GrantsEU:ENFUMOSA1996coPI,BIOAIR2006coPI,UBIOPRED2009IMIcoPI,AIRPROM2010coPI
GrantsFr:PHRC1997PI,ANR2007coPI,ANRcoPI2007,PHRCreg2012PI,ANR2013PI
Manyindustrialgrantsfromdifferentdrugscompaniesincludingsomeunrestrictedgrantsforresearch
Awards/Lectures
• 1988:LauréatdelaFacultédeMontpellierI,PrixdethèseArmet
• 1988:Médailled’ordesHôpitauxdeMontpellier,lauréatdesHôpitaux
• 1989:Internationaltravelgrant(AAAI);1990:PrixAllergie2000
• 2014:FERS;2016;prixdelaFondationdelarecherchemédicaleprixBPCOPettay
Relevantthesissupervisionhistory.Publicationswihallstudents
NathalieCarayol(2001),post-docatCollègedeFrance(Paris)
CarolineBonnans(2002),CR2Inserm(nonactivestatus,RinatPfizerSanFrancisco)
ArnaudBourdin(2006),PU-PH(CHUMontpellierandInsermU1046)
DelphineGras(2007),post-docUMRInsermU1067(Marseille)
YaëlGernez(2011),ResidentPhysicianatAlamedaCountyHospital(SanFrancisco)
KhuderAlagha(2015),MD(Montpellier)
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