男性不育相关蛋白mlh1和mir-383在精子发生中的功能研究-study on the function of male infertility related proteins ml h1 and mir - 383 in spermatogenesis.docx

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2018-07-27 发布于上海
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男性不育相关蛋白mlh1和mir-383在精子发生中的功能研究-study on the function of male infertility related proteins ml h1 and mir - 383 in spermatogenesis.docx

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男性不育相关蛋白mlh1和mir-383在精子发生中的功能研究-study on the function of male infertility related proteins ml h1 and mir - 383 in spermatogenesis

ToidentifythepotentialfunctionalmiRNAs,themiRNAexpressionprofilesoftestesofNOApatientsandnormalcontrolswereperformedbyusingmicroarraytechnologies.WidespreadderegulationofmiRNAsinNOApatientswasfound,with154differentiallydown-regulatedand19up-regulatedmiRNAs.AmongthedifferentiallyexpressedmiRNAs,miR-383whoseexpressionwasrestrictedtothespermatogoniaandspermatocytes,wassignificantlydown-regulatedinthetestesofMApatients.LossofmiR-383wasassociatedwithhyperactiveproliferationofgermcellsinMApatients.SilencingofmiR-383inNTera-2(testicularembryonalcarcinoma)cellsenhancedproliferativeactivity,promotesG1/Stransitionandinhibitsbasalapoptosis,whileoverexpressionofmiR-383reversedtheseeffects.Furthermore,miR-383’sfunctionaleffectsweremediatedthroughtargetingatumorsuppressor,interferonregulatoryfactor-1(IRF1),andmiR-383expressionwasnegativelycorrelatedwithIRF1proteinexpressioninvivo.miR-383inhibitedIRF1expression,whichconsequentlydown-regulatedcriticalcellcycle-relatedgenes,cyclinD1,CDK2andp21atthetranscriptionallevel.Down-regulationofIRF1orcyclinD1,butnotCDK2,enhancedmiR-383-mediatedeffects,whilesilencingofp21partiallyinhibitedmiR-383’effects.Ontheotherhand,miR-383increasedproteasome-dependentdegradationofCDK4,andultimatelyledtodown-regulationofpRbphosphorylation.Therefore,abnormalmiR-383-IRF1-pRbpathwaymaycontributestothedysregulationofspermatogonialproliferationinMApatientsandpotentiatetheconnectionsbetweenmaleinfertilityandtesticularcancer.Inconclusion,theresultsinthisstudyrevealedthenormalinterferencepatternamongMLH1fociandtheroleofmiR-383ingermcellproliferation.Theseresultscouldhelptofurtherunderstandingoftheunderlyingcausesofthedefectsinhomologousrecombinationand/orimbalancebetweenproliferationandapoptosisofgermcellsinNOApatients.Keywords:maleinfertility,MLH1,homologousrecombination,crossoverinterference,miR-383,germcellproliferationandapoptosis,testicularcancerIV中国科学技术大学学位论文原创性声明本人声明所呈交的学位论文,是本人在导师指导下进行研究工作所取得的成果。除已特别加以标注和致谢的地方外，论文中不包含任何他人已经发表或撰写过的研究成果。与我一同工作的同志对本研究所做的贡献均已在论