高級(jí)病理生理學(xué)課件 生物鐘講課

生物鐘基因與疾病

Circadiangenesanddiseases陸超西7號(hào)樓208室luchao@CircadianRhythmofSleepDays1234The

term"circadian",wascoined

byFranz

HalbergThetermcircadiancomesfromtwoLatinwordsnamely “circa”meansaround “diem/dies”meansday

Circadianmeans“approximatelyone

day’’同步(CircadianEntrainment)PhasecontrolPeriodcontrol自發(fā)性(Selfgenerated)：并非正好24小時(shí)/周期生物鐘的特征Mouseactivityentrainstolight10minsoflightperdayaresufficienttoresettheclock12hlight:12hdark24hdark10minlightClockintheBrainOverwhelmingevidenceindicatesthatthesuprachiasmaticnucleus(SCN),apairedstructurelocatedintheanteriorhypo-thalamuscontainsacircadianpacemaker.CircadianrhythmsareabolishedwithcompletelesionsoftheSCN.SCNtransplantsintothethirdventricleandhypothalamusrestoresrhythmicityinpreviouslyarrhythmicanimals.ThemammaliancircadiantimingsystemHypothalamusThepairedsuprachiasmaticnuclei(SCN)ofthehypothalamusistheprimarybiologicalclockregulatingcircadianrhythmsinmammals.Retino-hypothalamictractWelshFig05video.movRonKonopka生物鐘基因Clock突變小鼠Science.29,1994;264(5159):719–725JOSEPHTAKAHASHIWildtypeClock+/-Clock-/-Bmal1ClockPeriodCryptochromeBMALCLOCKPERCRYCircadianClockManipulations:ActivityWildTypeClockMutantsBmalKnockoutsVitaternaetal.,Science94;McDearmonetal.,Science06FergalCetal.CancerLetters,Volume342,Issue1,2014,9-18E-boxes(5′-CACGTG-3′)E′-boxes(5′-CACGTT-3′)Cell.1997,16;89(4):641–653Shimomuraetal.eLife2013;2:e00426.NHuangetal.Science2012;337:189-194PublishedbyAAASbasichelix-loop-helixPER-ARNTSIM(bHLH-PAS)NHuangetal.Science2012;337:189-194NHuangetal.Science2012;337:189-194PublishedbyAAASNHuangetal.Science2012;337:189-194MutationsthatreducerepressionofCLOCK:BMAL1transactivationbyCRYlocalizetoCLOCKPAS-BHIloop.NHuangetal.Science2012;337:189-194PublishedbyAAASNATUREREVIEWS|NEUROSCIENCEVOLUME4|AUGUST2003|649睡眠障礙與生物鐘DailyprofilesofexpressionofclockgenesBmal1,Cry1,Per2andRev-erbαinthemouseSCNatthepostnatalday1(P1),P3,P5.

LipidsHealthDis.2010;9:22.LipidsHealthDis.2010;9:22.DailyprofilesofexpressionofclockgenesBmal1,Cry1,Per2andRev-erbαinthemouseheartatthepostnatalday1(P1),P3,P5.BedontJL,

Blackshaw.FrontSystNeurosci.2015May8;9:74Age-relatedChangesinSleepPatternMELATONINNIGHTAnnalsofMedicine,2014;46:208–220ExplainingshiftlagandjetlagNotwelladaptedtoabruptshiftsindaylengthasinnaturedaylengthchangesslowly.Coren(1996)–acultureshifthappenedatthestartofthe20thcenturywhenelectriclightingbecamewidelyavailableFactoriesandofficescouldworkroundtheclock–introducingshiftworkandlongerworkinghours.SocialactivitiescouldalsoextendlaterintothenightWesleep1.5hrslessthan100yearsagoleadingtomildsleepdeprivationTREATMENTOFCIRCADIANRHYTHMDISORDERS

Behaviortherapy

oradviceabout

sleephygiene.Avoidnaps,caffeine,andotherstimulants.Bright

lighttherapyBlueblockingglassestherapyMedicationssuchas

melatonin

and

modafinil

(Provigil)Tasimelteon

hasbeenproveneffectiveinPhaseIIItrials.Sleepphasechronotherapy

生物鐘基因與腫瘤LoningFu,HelenePelicano,JinsongLiu,PengHuang,ChengChiLeeTheCircadianGenePeriod2PlaysanImportantRoleinTumorSuppressionandDNADamageResponseInVivoCell,Volume111,Issue1,2002,41-50TheCircadianGenePeriod2PlaysanImportantRoleinTumorSuppressionandDNADamageResponseInVivoCell,Volume111,Issue1,2002,41-50CancerLetters,Volume342,Issue1,2014,9-18

INTERNATIONALJOURNALOFONCOLOGY44:364-370,2014

INTERNATIONALJOURNALOFONCOLOGY44:364-370,2014生物鐘與代謝性疾病Tureketal.SCIENCEVOL30813MAY20051043SCIENCEVOL30813MAY20051043SCIENCEVOL30813MAY20051043Ahigh-fat(HF)dietlengthensthecircadianperiodinmice.SummaKC,andTurekFWAdvNutr2014;5:312S-319S?2014byAmericanSocietyforNutritionLight-phasefeedingleadstoincreasedweightgaininmicefedahigh-fatdiet.SummaKC,andTurekFWAdvNutr2014;5:312S-319S?2014byAmericanSocietyforNutritionScience13MARCH2015?VOL347ISSUE6227TRFimprovessleepandpreventsbodyweightgainwithoutreducingcaloricintake.DiurnalvariationofcircaidangenemRNAlevelsinSCNofC57BL/6JandapoE-/-mice.

LipidsHealthDis.2009;8:60.DiurnalvariationofcircadiangenemRNAinliversofC57BL/6JandapoE-/-mice.LipidsHealthDis.2009;8:60.LipidsHealthDis.2009;8:60.DiurnalvariationoftranscriptionfactorsPPARαandRXRαmRNAinliverofC57BL/6JandapoE-/-mice.

ComparisonofPrimaryStructuresofCLOCKandACTRCell125,497–508,May5,2006HATActivityDisplayedbyImmunoprecipitatedMyc-mCLOCKCell125,497–508,May5,2006Cell125,497–508,May5,2006SchematicModelofCLOCK-MediatedHistoneAcetylationandItsRolewithinthePhysiologicalPathwaysofCircadianRhythmicityCell125,497–508,May5,2006SIRT1RegulatesCircadianmRNAExpressionofdbpandper2GenesCell134,329–340,July25,2008Figure4.SIRT1IsRecruitedtotheE-boxandRegulatesCircadianHistoneAcetylationontheDbpGeneCell134,329–340,July25,2008Cell134,329–340,July25,2008InteractionofSIRT1withCLOCKSIRT1RegulatesBMAL1Lys537AcetylationCircadianDysfunctionandBMAL1UpregulatedAcetylationinLiver-SpecificSIRT1-DeficientMiceSCIENCEVOL3421NOVEMBER2013nicotinamidephosphoribosyltransferase(NAMPT)煙酰胺磷酸核糖基轉(zhuǎn)移酶1NOVEMBER5702013VOL342SCIENCEDiurnalMitochondrialRemodelingIsAbolishedinLBmal1KOLiverCellMetabolism