AssistantInvestigator,NIBS,Beijing，ChinaPhone：010-80726688-8605
Fax：010-80727512
E-mail：zhangerquan@nibs.ac.cn
教育经历Education2000–2004美国加州大学圣地亚哥分校分子病理专业博士
Ph.D.inMolecularPathology,UniversityofCalifornia–SanDiego,LaJolla,California,USA
1994–1997复旦大学生物化学专业硕士
M.S.inBiochemistry,FudanUniversity,Shanghai,China
1990–1994华东师范大学环境科学专业学士
B.S.inEnvironmentalScience,EastChinaNormalUniversity,Shanghai,China
工作经历ProfessionalExperience2011–北京生命科学研究所研究员
AssistantInvestigator,NationalInstituteofBiologicalSciences,Beijing,China
2006–2010美国诺华制药加州圣地亚哥研究院高级博士后研究员；兼美国加州大学圣地亚哥分校生物科学学院访问学者
InstituteFellow,GenomicsInstituteoftheNovartisResearchFoundation,SanDiego,California,USA;VisitingScholar,DivisionofBiologicalSciences,UniversityofCalifornia–SanDiego,LaJolla,California,USA
2004–2006美国加州斯科瑞普斯研究所博士后
PostdoctoralAssociate,TheScrippsResearchInstitute,LaJolla,California,USA
研究概述生物钟对人类行为与生理有广泛的调节作用。我们对生物钟研究领域各个方面都感兴趣，主要想回答三大问题：什么是生物钟？生物钟如何进行调控？研究生物钟有何重要意义？目前我们对以下几个子课题特别感兴趣：1.对于哺乳动物的生物钟而言，一个简单的模型就是转录因子形成的延迟负反馈系统：转录正因子CLOCK和BMAL1结合，激活转录负因子PERIOD（包括PER1,PER2,PER3；简称PER）和CRYPTOCHROME（CRY1,CRY2；简称CRY）。PER与CRY表达积累到一定程度会反过来抑制CLOCK-BMAL1的活性，从而导致PER-CRY表达降低，形成每循环约24小时的负反馈环路。早期的小鼠行为筛选以及最近的全基因siRNA筛选都显示有更多的生物钟基因存在。我们准备运用系统生物学结合小鼠遗传学方法研究新的生物钟基因及其调控转录的分子机理，更深入理解生物钟振荡器的相位，振幅，及周期。
2.视交叉上核（SCN）是负责生物钟调控的主要器官，位于下丘脑前端。前期研究表明，SCN中存在一种特异性的分子机制暂时不明的耦合机理，促使其内的生物钟异常强劲。我们准备运用合成生物学方法改造成纤维细胞，外加某种假设的耦合机理，使其变成SCN神经细胞。如获得成功，我们就不仅解释了耦合的分子机理，也会提供足够的材料作生化分析，用以更深层次的解释何以SCN区别于其它组织而作为生物钟调控的中心。
3.我们对生物钟如何调节进食行为很感兴趣。当前的假说是，在大脑中存在一个独立于SCN之外的“食物调控振荡器（FEO）”，用以整合生物钟和食物需求的信息。我们将与清华大学宋森研究员的课题组合作，运用最新颖的光学遗传学方法来寻找FEO。
4.生物钟失调会导致代谢紊乱。为了充分发挥本研究员以前做高通量筛选（HTS）的特长已及应用NIBS拥有的最先进的HTS设备，我们会用此技术开创几个探索性课题，用以了解生物钟对酒精代谢和脂肪肝形成的影响。从这些细胞筛选方法得到的假说，我们会进一步运用小鼠遗传学等体内方法来加以验证。
ResearchDescriptionCircadianclockregulateshumanbehaviorandphysiology.Weareinterestedinunderstandingallaspectsofcircadianrhythms:Whatistheclock?Howdoestheclockrun?Whyistheclockrelevant?Inparticular,wefocusonseveralprojectsindissectingtheclockmechanismandhighlightingitsbiological/biomedicalsignificance:1.Inasimplifiedmodel,transcriptionalactivatorsCLOCKandBMAL1stimulatePERIOD(PER1,PER2andPER3)andCRYPTOCHROME(CRY1,CRY2)repressorsthatfeedbackonCLOCK-BMAL1activity.Bothmousebehavioralandgenome-wideRNAiscreenssuggestthattherearemoreclockgenestobeidentified.Usingsystemsbiologyandmousegeneticsapproaches,weaimtounderstandthedetailedmolecularbasisoftranscriptionalregulationsonclockphase,amplitude,andperiod-length.
2.Suprachiasmaticnucleus(SCN)istheclockmasterorgan,locatedintheanteriorhypothalamus.PreviousstudiesindicatedthatthecouplingmechanismdistinguishestheSCNfromotherperipheraltissuesincontrollingtherobustnessoftheclock.Usingsyntheticbiologytools,weaimtoreconstitutefibroblastcells,anexemplarymodelforperipheralclocks,intoSCNneuronsbytransplantingthecouplingsystem.AsuccessfulrecapitulationofSCNpropertiesbymanipulatingfibroblastswillnotonlyoffermechanisticinsightsforthecoupling,butalsoprovidesufficientmaterialsforbiochemicalcharacterization,allowingustounderstandtheuniquenessofclockmasterregulation.
3.IncollaborationwithSenSonglaboratoryatTsinghua,wewillutilizeoptogenetictoolstohuntforapresumptiveFood-EntrainableOscillator(FEO)inthemousebrain,therebydissectingtherelationshipbetweenthecircadianclockandfeedingbehaviors.
4.Metabolicdisordersarelinkedtomalfunctionsofthecircadianclock.TofullybenefitfromthePI’sexpertiseonhigh-throughputscreening(HTS)andthe“state-of-the-art”HTSfacilityatNIBS,weplantoconductafewpilot/exploratoryprojectstounderstandtheclock’simpactsonalcoholmetabolismandfatty-liverdevelopment.Hypothesesgeneratedfromthesecell-basedscreenswillbefurthertestedinvivo.
发表文章Publications:1.Zhang,E.E.andKay,S.A.ClocksNotWindingDown:UnravelingCircadianNetworks.(2010)NatureReviewsMolecularCellBiology11:764-776{InvitedReview,10-yearAnniversarySeries}
2.Zhang,E.E.*,Liu,Y.*,Dentin,R.,Pongsawakul,P.Y.,Liu,A.C.,Hirota,T.,Nusinow,D.A.,Sun,X.,Landais,S.,Kodama,Y.,Brenner,D.,Montminy,M.andKay,S.A.CryptochromeMediatesCircadianRegulationofcAMPSignalingandHepaticGluconeogenesis.(2010)NatureMedicine16:1152-1156{FeaturedbyNatureMedicine,“Highglucose,nocry”(NewsandViews);HighlightedbyFacultyof1000,F1000Factor=8.0(MustRead)}
3.Hirota,T.,Lee,J.W.,Lewis,W.G.,Zhang,E.E.,Breton,G.,Liu,X.,Garcia,M.,Peters,E.C.,Etchegaray,J-P.,Traver,D.,Schultz,P.G.andKayS.A.High-ThroughputChemicalScreenIdentifiesaNovelPotentModulatorofCellularCircadianRhythmsandRevealsCKIasaClockRegulatoryKinase.(2010)PLoSBiology8:e1000559
4.Ko,C.H.*,Yamada,R.*,Welsh,D.K.*,Buhr,E.D.,Liu,A.C.,Zhang,E.E.,Ralph,M.R.,Kay,S.A.,Forger,D.andTakahashi,J.S.EmergenceofNoise-inducedOscillationsintheCentralCircadianPacemaker.(2010)PLoSBiology8:e1000513
5.Zhang,E.E.*,Liu,A.C.*,Hirota,T.*,Miraglia,L.J.,Welch,G.,Pongsawakul,P.Y.,Liu,X.,Atwood,A.,Huss,J.W.III.,Janes,J.,Su,A.I.,Hogenesch,J.B.,andKay,S.A.AGenome-widesiRNAScreenforModifiersoftheCircadianClockinHumanCells.(2009)Cell139:199-210{HighlightedbyFacultyof1000,F1000Factor=10.0(Exceptional);HighlightedbyCell,2012CollectiononCircadianRhythms}
6.Hagihara,K.*,Zhang,E.E.*,Ke,Y-H.*,Liu,G.,Liu,J-J.,Rao,Y.andFeng,G-S.Shp2actsdownstreamofSDF-1alpha/CXCR4inguidinggranulecellmigrationduringcerebellardevelopment.(2009)DevelopmentalBiology334:276-284
7.Lv,S.Q.,Zhang,K.B.,Zhang,E.E.,Gao,F.Y.,Yin,C.L.,Huang,C.J.,He,J.Q.andYang,H.AntitumorEfficiencyoftheCytosineDeaminase/5-FluorocytosineSuicideGeneTherapySystemonMalignantGliomas:anInVivoStudy.(2009)MedicalScienceMonitor15:BR13-20
8.Krajewska,M.,Banares,S.,Zhang,E.E.,Huang,X.,Scadeng,M.,Jahla,U.S.,Feng,G-S.andKrajewski,S.DevelopmentofDiabesityinMicewithNeuronalDeletionofShp2TyrosinePhosphatase.(2008)AmericanJournalofPathology172:1312-1324
9.Liu,A.C.,Tran,H.G.,Zhang,E.E.,Priest,A.,Welsh,D.K.andKay,S.A.RedundantFunctionofREV-ERBαandβandNon-EssentialRoleforBmal1CyclinginTranscriptionalRegulationofIntracellularCircadianRhythms.(2008)PLoSGenetics4:e1000023
10.Pan,Y.,Carbe,C.Powers,A.,Zhang,E.E.,Esko,J.D.,Grobe,K.,Feng,G-S.andZhang,X.BudSpecificN-SulfationofHeparanSulfateRegulatesShp2-DependentFGFSignalingduringLacrimalGlandInduction.(2008)Development135:301-310
11.Ke,Y.*,Zhang,E.E.*,Hagihara,K.,Wu,D.,Pang,Y.,Klein,R.,Curran,T.,Ranscht,B.andFeng,G-S.DeletionofShp2intheBrainLeadstoDefectiveProliferationandDifferentiationinNeuralStemCellsandEarlyPostnatalLethality.(2007)MolecularandCellularBiology27:6706-6717
12.Liu,A.C.*,Welsh,D.K.*,Ko,C.H.,Tran,H.G.,Zhang,E.E.,Priest,A.,Buhr,E.D.,Singer,O.,Meeker,K.,Verma,I.M.,Doyle,F.J.III.,Takahashi,J.S.andKay,S.A.IntercellularCouplingConfersRobustnessAgainstMutationsintheSCNCircadianClockNetwork.(2007)Cell129:605-616
13.Nguyen,T.V.,Ke,Y.,Zhang,E.E.andFeng,G-S.ConditionaldeletionofShp2tyrosinephosphataseinthymocytessuppressesbothpre-TCRandTCRsignals.(2006)JournalofImmunology177:5990-5996
14.Bard-Chapeau,E.A.,Yuan,J.,Dronin,N.,Long,S.,Zhang,E.E.,Nguyen,T.V.andFeng,G-S.ConcertedFunctionsofGab1andShp2inLiverRegenerationandHepatoprotection.(2006)MolecularandCellularBiology26:4664-4674
15.Ke,Y.,Lesperance,J.,Zhang,E.E.,Bard-Chapeau,E.A.,Oshima,R.G.,Muller,W.J.andFeng,G-S.ConditionaldeletionofShp2inthemammaryglandleadstoimpairedlobulo-alveolaroutgrowthandattenuatedStat5activation.(2006)JournalofBiologicalChemistry281:34374-34378
16.Dong,X.P.,Li,X.M.,Gao,T.M.,Zhang,E.E.,Feng,G.S.,Xiong,W.C.andMei,L.Shp2IsDispensableintheFormationandMaintenanceoftheNeuromuscularJunction.(2006)Neurosignals15:53-63
17.Bard-Chapeau,E.A.,Hevener,A.L.,Long,S.,Zhang,E.E.,Oliesky,J.andFeng,G-S.DeletionofGab1intheLiverLeadstoEnhancedGlucoseToleranceandImprovedHepaticInsulinAction.(2005)NatureMedicine11:567-571
18.Zhang,E.E.,Chapeau,E.,Hagihara,K.andFeng,G-S.NeuronalShp2TyrosinePhosphataseControlsEnergyBalanceandMetabolism.(2004)ProceedingsoftheNationalAcademyofSciencesU.S.A.110:16064-16069
19.Lai,L.A.,Zhao,C.,Zhang,E.E.andFeng,G-S.Chapter14:TheShp-2TyrosinePhosphatase.TopicsinCurrentGenetics:ProteinPhosphatasesbyJ.ArinoandD.Alexander,(2004)Heidelberg:Springer-VerlagPublisher,ISBN:3-540-20560-8,pp275-299{bookChapter}
20.Chen,Y.,Wen,R.,Yang,S.,Schuman,J.,Zhang,E.E.,Yi,T.,Feng,G-S.andWang,D.IdentificationofShp2asaStat5APhosphatase.(2003)JournalofBiologicalChemistry278:16520-16527
专利申请PatentApplication:Feng,G-S.andZhang,E.E.“ModulatorsofShp2tyrosinephosphataseandtheiruseinthetreatmentofbodyweightdisorders”.USPTOPublicationDocumentNo.20080058431;PCTPublicationNo.WO/2005/094314;Int’lApplicationNo.PCT/US2005/010380;PriorityData60/556,56426-03-2004US
