紫杉醇减少脊髓损伤后疤痕形成并促进轴突再生_精品文档PPT推荐.pptx

紫杉醇减少脊髓损伤后疤痕形成并促进轴突再生_精品文档PPT推荐.pptx

《紫杉醇减少脊髓损伤后疤痕形成并促进轴突再生_精品文档PPT推荐.pptx》由会员分享，可在线阅读，更多相关《紫杉醇减少脊髓损伤后疤痕形成并促进轴突再生_精品文档PPT推荐.pptx（37页珍藏版）》请在冰豆网上搜索。

DOI:

10.1126/science.1201148,Reporter:

*Supervisor:

*SecondarySupervisor:

*,Backgrounds,Hypertrophicscarringandpoorintrinsicaxongrowthcapacityconstitutemajorobstaclesforspinalcordrepair.Microtubuledynamicsregulatekeyprocessesduringscarring,includingcellproliferation,migration,anddifferentiationaswellasintracellulartraffickingandsecretionofextracellularmatrix（ECM）molecules（1,2）.Moreover,moderatemicrotubulestabilizationpreventsaxonalretractionandswellingoftheaxontipaftercentralnervoussystem（CNS）injury（3）andstimulatesaxongrowthofculturedneurons（4）,enablingthemtoovercomethegrowthinhibitoryeffectofCNSmyelin（3）.,Assumptions,TheyhypothesizedthatmoderatemicrotubulestabilizationwithTaxol,anapproveddrug,wouldfacilitateaxonalregenerationafterspinalcordinjury（SCI）bydecreasingscarformationandenhancingintrinsicaxonalgrowth.,Methods,TheyfirstexaminedwhetherTaxoltreatmentreducedscarringafterSCI.Adultratsunderwentadorsalhemisectionattheeighththoracicspinalcordlevel;

Taxol（256ng/day）wascontinuouslydeliveredattheinjurysiteusinganintrathecalcatheterconnectedtoanosmoticminipump.,Whathappened7dayslater？

FaridaHellaletal.Science2011;

331:

928-931,PublishedbyAAAS,Fig.1Taxoldecreasesscarringinducedbyspinalcordinjury.（A）Representationoflesionedspinalcord（box）.（BandC）Midsagittalsectionsoflesionsitefromratstreatedwith（B）vehicleor（C）Taxol（256ng/day）7daysafterinjury.Scalebars,300m.（D）Taxolsignificantlydecreasesfibroticscarring（expressedaspercentageofvehiclecontrol;

n=12ratspergroup;

*P=0.002;

two-tailedttest）withoutaffectingglialcompaction（28daysafterinjury）（E）orinjurysize（F）（n=7to10ratspergroup;

P=0.951;

two-tailedttest）.DataexpressedasmeanSEM.GFAP,glialfibrillaryacidicprotein.,FigureS1:

Taxoldecreasesfibronectin,NG2proteoglycanandcollagenIVaccumulationinducedbyspinalcordinjury（A）Representationoflesionedspinalcord（box）.（B-D）Mid-saggitalsectionsoflesionsitefromrattreatedwithVehicleorTaxolat7dayspost-injury.TaxoldecreasesECMdepositinthecoreofthelesionasassessedbyfibronectin（B）,collagenIV（C）andNG2proteoglycan（D）immunostainings.Thedashedlinesoutlinethelesionsite.Scalebar,150m.,（A）Representationoflesionedspinalcord（box）.（B-C）Mid-saggitalsectionsoflesionsitefromratstreatedwithVehicleorTaxol（7dayspost-injury）stainedwithDAPI（B）andphospho-histoneH3（C）.Scalebar,150m.（D）Taxoldoesnotaffectcellproliferationinducedbyspinalcordinjury.ResultsexpressedasmeanSEM;

p=0.591;

two-tailedttest（n=7animalspergroup）.,FigureS2:

Taxoldoesnotinterferewithproliferation,FigureS3:

Taxoldoesnotinduceapoptosisintheinjuredspinalcord（A）Representationoflesionedspinalcord（box）.（B-C）Mid-saggitalsectionsoflesionsitefromratstreatedwithVehicleorTaxolstainedwithTUNELat3（B）and7（C）daysafterdorsalhemisectioninjury.Scalebar,150m.（D）Taxoldoesnotaffectthecelldeathinducedbyspinalcordinjury.ResultsexpressedasmeanSEM;

3dpi:

p=0.628;

7dpi:

p=0.679;

two-tailedttest（n=7animalspergroup）,Conclusion1:

Atlowdoses,Taxolreducedfibroticscarringbymechanismsindependentofcellproliferationorapoptosis.,2.Then,theyexaminedwhetherstabilizingthemicrotubulenetworkhindersTGF-signalingandattenuatesfibrogenesis.,AkeyeventinfibroticscarringafterCNSinjuryistheactivationoftransforminggrowthfactor（TGF-）signaling.FollowingSCI,TGF-expressiondramaticallyincreases,whichfavorsfibrosis（1012）.Integrityofthemicrotubulenetworkiscrucialforthetransductionofthissignal（13）.Smad2,thedownstreameffectoroftheTGF-pathway,bindstomicrotubulesthroughconventionalkinesin-1（14）.,Fig.2.TaxoldampensTGF-signaling.（A）Taxoltreatmentincreasestotaltubulinanddecreasestyrosinatedtubulininthelesionsite，enablingkinesin-1tobindtightlytomicrotubules（15）.（B）Kinesin-1enrichmentinmicrotubulefractionofTaxol-treatedlesionsite.（C）His-Smad2bindstokinesin-1andendogenousSmad2coimmunoprecipitateswithkinesin-1（D）ofbrainandspinalcordextracts.,Fig.2.TaxoldampensTGF-signaling.（EandF）Taxolaltersmicrotubule-basedcargotransport.（E）Overlayofcolorcodedtimeseriesofredfluorescentprotein（RFP）labeledperoxisomesboundtothekinesin-1（KIF5）motordomainuponRapalogaddition.Bluemarkstheinitialdistribution;

theredgradientshowsthedistributionovertime（30min）.Scalebars,10mm.（F）Timetracesofradiusofcircleenclosing90%oftotalfluorescenceintensityforKIF5-ordyneinadaptor（BICDN）linkedperoxisomes.MeanTSEMof5to8COS-7cellspercondition（P=0.004;

two-tailedttestforbothKIF5andBICDN）.,ThissuggestingthatTaxolwouldhinderSmad2trafficking.,Indeed,inT