临床科研思路非编码RNA与自身免疫病课题设计的考虑几个要素不同级别的创新思考创新性：结合重要的临床、科学问题意义：样本库建设和临床数据库建设可行性（没钱没条件）浏览文献，把握发展方向开放合作、整合资源、实现双赢数据挖掘Part1.miR-146a和IFN通路不得不说的故事82statisticallydifferentiallyexpressedmiRNAsinlupuspatient(48miRNAswithfoldchange≥1.5)lowerinpatients;higherinpatients20patientsvs.22controlsmiR-21，miR-146a，miR-125a‥‥‥表达谱研究发现SLE中一组miRNA表达异常STIMULI(LPS)TRAF6miR-146aIRAK1DOWNSTREAMEVENTS发现miR-146a是重要的生物标志物，可作为SLE病情活动的评估指标0481205101520253035r=-0.3815P=0.0081renal-SLEDAIscorerelativeexpressionlevel-1491419245101520253035r=-0.2882P=0.0247SLEDAIscorerelativeexpressionlevelproteinuria(-)proteinuria(+)05101520253035P=0.0271relativeexpressionlevelNCSLE-InactiveSLE-Active01020304050607080P=0.0080P=0.0006P<0.0001relativeexpressionlevelSLEDAI:SLEdiseaseactivityindexArthritis&Rheumatism.2009InterferonsignaturemiR146的表达水平和SLE病人干扰素通路的活化程度负相关-109019029039049005101520253035r=-0.3073P=0.0378IFNscorerelativeexpressionlevelArthritis&Rheumatism.2009TRAF6IRF9typeIIFNgenesMyD88IRAK1TLR7-9IRF7/IRF5STAT1/STAT2IFNinduciblegenesISREpathogenTRAF6IRF9typeIIFNgenesMyD88IRAK1TLR7-9IRF7/IRF5STAT1/STAT2IFNinduciblegenesISREpathogenmiR-146aOverexpressionofmiR-146arepressestheproductionoftypeIIFNsinnormalPBMC.SilencingofmiR-146aaugmentstheproductionoftypeIIFNsinPBMC.miR-146a作为负反馈调节分子，可抑制Toll样受体诱导的I型干扰素的产生TRAF6IRF9typeIIFNgenesMyD88IRAK1TLR7-9IRF7/IRF5STAT1/STAT2IFNinduciblegenesISREpathogenTRAF6IRF9typeIIFNgenesMyD88IRAK1TLR7-9IRF7/IRF5STAT1/STAT2IFNinduciblegenesISREpathogenmiR-146a293T/ISREPBMCmiR-146a可抑制干扰素下游通路的活化miR-146a对干扰素通路调节的分子机制研究-------鉴定了miR-146a所作用的关键靶向分子TRAF63’UTRmiR-146aIRAK13’UTRmiR-146aTRAF63’UTRmiR-146aIRAK13’UTRmiR-146aTRAF63’UTRmiR-146aIRAK13’UTRmiR-146aTRAF63’UTRmiR-146aIRAK13’UTRmiR-146a√√Bioinformaticsearch29signalingproteinsinthepathwayTRAF6IRF9typeIIFNgenesMyD88IRAK1TLR7-9IRF7/IRF5STAT1/STAT2IFNinduciblegenesISREpathogenTRAF6IRF9typeIIFNgenesMyD88IRAK1TLR7-9IRF7/IRF5STAT1/STAT2IFNinduciblegenesISREpathogenmiR-146atargetsmultiplekeycomponentsinthesignalingcascade!体外干预SLE病人免疫细胞中miR-146a的表达，可抑制SLE病人干扰素通路的过度活化，说明miR-146a是潜在的药物治疗靶点IFIT3MX1OAS1050100150200250300patient#3relativeexpressionlevelIFIT3MX1OAS105010015020025095010001050patient#2relativeexpressionlevelIFIT3MX1OAS10100200300400500vectormiR-146arelativeexpressionlevelpatient#1体外干预SLE病人免疫细胞中miR-146a的表达，可抑制SLE病人干扰素通路的过度活化，说明miR-146a是潜在的药物治疗靶点IFIT3MX1OAS1050100150200250300patient#3relativeexpressionlevelIFIT3MX1OAS105010015020025095010001050patient#2relativeexpressionlevelIFIT3MX1OAS10100200300400500vectormiR-146arelativeexpressionlevelpatient#1被Facultyof1000medicine两位专家所推荐MichaelCentola指出“这篇论文是非常重要的发现，第一次阐述了microRNA在自身免疫病中的作用并且开启了有关IFN与狼疮非常复杂生物学研究的新方向。miR-146a可作为新的狼疮诊断的生物标志物和狼疮治疗药物靶点”。MichaelMcdermott指出：“尽管该研究聚集于狼疮，但对其它自身免疫病的研究也具有潜在重要意义，基于microRNA的调节性治疗将减轻狼疮免疫过度活化且克服目前免疫抑制治疗造成宿主免疫防御缺陷的弊端”。Part2.miRNA表达调控紊乱的机制研究Characterizationoft...
