新型非基因疗法可治疗先天性耳聋

时间 : 2009-11-28 02:57:19 来源：www.bioon.com

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Emory大学科学家通过老鼠实验发现很大一部分基因造成的耳聋患者的听力可望得到恢复。他们发现，在老鼠耳蜗中增加一种connexin26蛋白能补偿另一种蛋白――connexin30的缺失。10年前科学家就已经知道connexin26的变异会导致新生儿耳聋。耳鼻喉和细胞生物学副教授XiLin是主要负责人，他们的研究结果发表在了最新的《美国国家科学院院刊》（PNAS）上。在正常人体内，connexin26和connexin30同时作用以形成耳蜗中的关键性结构，但是当其中一种蛋白质缺失时，这一结构就会失去作用，而且使得耳蜗中的毛细胞死亡，因此就无法将声音转化为神经冲动。即使科学家知道connexin26可能是导致先天耳聋的原因，但是其中的机理并不清楚。通过和来自Bonn大学的科学家合作，Lin建立了一套假说。他说：“耳聋的形成有两种可能，一种是耳蜗中的关键结构有特殊的生物物理性质，无法只由一种connexin蛋白形成，另一种是connexin蛋白的变异导致结构形成时供给的减少。”通过在缺失connexin30的小鼠中补充connexin26，Lin的小组证明了后一种假说是正确的。通过增加connexin26，听力得到了恢复，而且毛细胞的死亡也没有发生。Lin的小组目前在研究connexin缺乏造成的耳聋能否在老鼠中得到治疗，或者connexin26的缺乏能否通过connexin30补偿。Lin表示，目前研究听力损失的科学家主要将注意力放在基因疗法上，但是基因疗法成功例子太少了，或许这并不是很好的治疗手段。而Lin的发现表明促进connexin26的药物或许才是真正需要的。

部分英文原文：

Restorationofconnexin26proteinlevelinthecochleacompletelyrescueshearinginamousemodelofhumanconnexin30-linkeddeafness

ShoebAhmad*,WenxueTang*,QingChang*,YanQu*,JillHibshman*,YuhuaLi

Departmentsof*OtolaryngologyandEditedbyMichaelV.L.Bennett,AlbertEinsteinCollegeofMedicine,Bronx,NY,andapprovedNovember28,2006（receivedforreviewAugust9,2006）AbstractMutationsingenescodingforconnexin26（Cx26）and/orCx30arelinkedtoapproximatelyhalfofallcasesofhumanautosomalnonsyndromicprelingualdeafness.Cx26andCx30arethetwomajorCxisoformsfoundinthecochlea,andtheycoassembletoformhybrid（heteromericandheterotypic）gapjunctions（GJs）.ThismoleculararrangementimpliesthathomomericGJswouldremaininthecochleaifoneofthecoassemblypartnersweremutatedresultinginnullexpression.WegeneratedmiceinwhichextracopiesoftheCx26geneweretransgenicallyexpressedfromamodifiedbacterialartificialchromosomeinaCx30C/Cbackground.IntheabsenceoftheCx30gene,Cx26expressedfromextraallelescompletelyrestoredhearingsensitivityandpreventedhaircelldeathindeafCx30C/Cmice.TheresultsindicatedthathybridGJsconsistingofCx26andCx30werenotessentialfornormalhearinginmiceandsuggestedthatup-regulationofCx26orslowingdownitsproteindegradationmightbeatherapeuticstrategytopreventandtreatdeafnesscausedbyCx30mutations.Connexins（Cxs）areafamilyofmembraneproteinsconstitutinggapjunctions（GJs）,whichfacilitateintercellularcommunication.TheimportanceofCxsinhearinghasbeenrevealedbygeneticstudiesshowingthatmutationsinCxgenesareamongthemostcommonformsofhumangeneticdefects,resultinginhearingimpairmentsinmillionsofpatientswitheitherautosomaldominantorrecessivedeafness（1C3）.Inmanyethnicpopulations,mutationsinCx26（1,4）,Cx30（5,6）,andotherCxgenes（7,8）havebeenlinkedtoapproximatelyhalfofinheritedprelingualnonsyndromicdeafnesscases.ThemostcommonlyfoundmutationsaredeletionsofeitherCx26（e.g.,35delGor235delC;refs.9and10）orCx30（e.g.,GJB6-D13S1830;ref.6）thateffectivelyeliminategeneexpression.AnimalmodelsofconditionalknockoutoftheCx26gene（11）andtargeteddeletionofCx30-codingDNA（12）areavailable,bothofwhichresultindeafnessinhomozygousmice.BecauseGJsinthecochleaarecoassembledfromCx26andCx30（13C15）,wesuspectedthatdeletionofonemajorcochlearCxgenemaynoteliminateGJintercellularcouplinginthecochlea.Consistentwiththisspeculation,immunocytochemicalresultsrevealedthatthecellularexpressionpatternoftheremainingCxinthecochleaeofCx26andCx30mutantmiceisunalteredcomparedwithWTanimals（11,12）.Apparently,homomericGJsremaininthecochleaoftheseCxmutantmice.ThesedataraisethequestionwhygeneexpressionfromasingleCxisoformisinsufficientfornormalhearing.HeteromericassemblyofCxsisrequiredfornormalfunctionsinsometissues（e.g.,thelensintheeye;seeref.16）.ThesedataobtainedfromanonauditorysystemsuggestthatinappropriatebiophysicalpropertiesofthehomomericGJchannelsinthecochleamayunderliedeafnesscausedbyCxmutations.ItisalsopossiblethatthetwomajorcochlearCxsarecoregulatedateitherthetranscriptionaland/orthetranslationallevel,suchthattheabsenceofoneCxgenesignificantlyaffectstheexpressionoftheother.Anothersimpleexplanationwouldbehaploinsufficiencycausedbygenedeletionofoneofthetwocoassemblypartners.IfaninsufficientnumberoffunctionalGJchannelscausesdeafness,wehypothesizedthatdeafnessmightbecorrectedbyincreasingtheexpressionoftheremainingcoassemblypartner.Therefore,weinvestigatedwhetherthehearingofdeafCx30C/CmicecouldberestoredbygeneticallyoverexpressingtheCx26gene.英文全文链接：http://www.pnas.org/cgi/content/full/104/4/1337相关报道:耳聋耳聋与CX26基因缺陷有关从耳蜗找到干细胞治疗神经性聋

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