转博材料培养计划复旦开题报告

Galectin-3在非性脂肪性肝病脂肪变中的作用及机制研与导师（教研室或学科组）非性脂肪性肝病（non-alcoholicfattyliverdisease，NAFLD）与肥胖、、高脂血症、高血steatohepatitis，NASH，21世纪全球重要的公共健康问题之一，但目前对其发病机制仍然知之甚少，近年来，越来越多的证galectin3NAFLD的发生发展中发挥至关重要的作用。（Galectn3,2935kDa包括一个长的氨基末端结构域和羧基末端的单一碳水化合物识别结构域以及两者之间的脯氨酸、甘氨[5]al3要位于胞核可通过型途径分泌到胞外组织间隙[6]al3的结构征使其能通过其与细胞外和细剂[710]。发挥重要作用。Nomoto等，Gal3敲除小鼠在6个月龄时自发发生肝脏脂肪变性[11]。但在Iacobini等的一项研究中，当饲喂致动脉粥样硬化高脂饮食时，Gal3NASH的发展Gal3NASH的炎症低[13]。此外，Gal3敲除在体外肝星状细胞培养和体内四氯化碳（CCl4）CCl4诱导的小鼠肝纤维化[14]。的研究表明,Gal3可以直接与肝细胞表面的胰岛素受体结合并抑制下游的信号转导，因而可能成为肥胖诱导的胰岛素抵抗与炎症之间的靶向联系。这些研究为Gal3在究，现有的存在相互的结论，这可能与动物饲喂方案和环境差异等诸多因素相关，但是以往的Gal3调控肝脏脂肪代谢引起肝脂肪变性的作用机制。肝脂变性是FLD发生的最早阶段其特征是甘油三酯在肝脏中的积聚肝脏中大约0％含量的甘油三酯来源于脂肪组织分解产生的游离脂肪酸( fattycid,)，26％来于肝细胞从头合成脂肪，而15来源于饮食[5]。A在肝脏中的含量增加以及A诱导的肝内质网应激是D发生和发展的两个关键致病过程[6]。其中，固醇调节元件结合蛋白1c（erolregulatoylementbindngprotein1c，P1c）是调节肝脏脂质合成的主要转录因子，它在成熟后易位于核内，转录上调包括乙酰辅酶羧化酶（acetylCoAcaroxylase1，C、脂肪酸酶（fattyacide，）和硬脂酰辅酶A去饱和酶1（yloenzymeAdeturae1,CD1在内的脂肪生成[7。P1c上调会促进脂肪生成从而促进肝细胞A内流的增加[1]P活化蛋白激（activatedproeinkinase，是丝氨酸/苏氨酸激酶的关键细胞能量和营养物传感器K在真核生物中通常表达为由催化亚基α、两个调节亚基β和γ组成的异三聚体复合物，并通过α亚基Thr172的磷酸化激活[1]。许多研究表明，K是肝脂肪形成的关键调节因子，使得该酶成为治疗肝脂肪变性的潜在治疗靶点[0]。K活化使C磷化并失活从而急剧减少脂肪酸合成[1]K化后可以通过减少1c的转录激活来减少脂肪酸合成最近的研究显示K可以在2位点上磷化P1抑制其切割和核易位并抑制高葡萄糖条件下的肝细胞靶的表达导致脂肪生成和脂质积累减少[2]外有研究证实K活化对肝细胞脂质诱导的内质网(endocreicuum,R)应激的负调节作用[2,23]ER应表现为内质网内稳态的破坏，其特征是葡萄糖调节蛋白7（glucosergulatedpotin78，8，C/EBP同源蛋白（C/EBPhomlogousprotein，CP）和磷酸化蛋白激酶样ER激酶（phosphorylatedproteinkinase-likeERkinase，p-PERK）等标志物的高表达，ER应激促进肝脏脂肪生成和脂质积累[2425],FFANAFLD的肝AMPK-SREBP-1-ACC1-FASGal3FFA诱导脂肪变的作用，分析AMPK途径活化是否作用于ERGRP78CHOP和p-PERKAMPKGal3ER应激相互作用的机制。Gal3对肝细胞脂质代谢的作用与机制研究是其能否作为NAFLD治疗靶点的问题，对于控制NAFLD的发病和进展具有重要意义。YounossiZM,KoenigAB,AbdelatifD,etal.Globalepidemiologyofnonalcoholicfattyliverdisease-Meta-yticassessmentofprevalence,incidence,and es[J].Hepatology,2016,64(1):73-84.WreeA,BroderickL,CanbayA,etal.FromNAFLDtoNASHtocirrhosis-newinsightsintodiseasemechanisms[J].NatRevGastroenterolHepatol,2013,10(11):627-636.CohenJC,HortonJD,HobbsHH.Humanfattyliverdisease:oldquestionsandnewinsights[J].Science,StarleyBQ,CalcagnoCJ,HarrisonSA.Nonalcoholicfattyliverdiseaseandhepatocellularcarcinoma:aweightyconnection[J].Hepatology,2010,51(5):1820-1832.BarondesSH,CooperDN,GittMA,etal.Galectins.Structureandfunctionofalargefamilyofanimallectins[J].JBiolChem,1994,269(33):20807-20810.MenonRP,HughesRC.DeterminantsintheN-terminal sofgalectin-3forsecretionbyanovelpathwaycircumventingtheendosmicreticulum-Golgicomplex[J].EurJBiochem,1999,264(2):569-576.DennisJW,NabiIR,DemetriouM.Metabolism,cellsurfaceorganization,anddisease[J].Cell,PartridgeEA,LeRoyC,DiGuglielmoGM,etal.RegulationofcytokinereceptorsbyGolgiN-glycanprocessingandendocytosis[J].Science,2004,306(5693):120-124.PuglieseG,IacobiniC,PesceCM,etal.Galectin-3:anemergingall-outyerinmetabolicdisordersandtheircomplications[J].Glycobiology,2015,25(2):136-150.IacobiniC,AmadioL,OddiG,etal.Roleofgalectin-3indiabeticnephropathy[J].JAmSocNephrol,2003,14(8Suppl3):S264-S270.NomotoK,TsuneyamaK,AbdelAH,etal.Disruptedgalectin-3causesnon-alcoholicfattyliverdiseaseinmalemice[J].JPathol,2006,210(4):469-477.IacobiniC,MeniniS,RicciC,etal.Galectin-3ablationprotectsmicefromdiet-inducedNASH:amajorscavengingroleforgalectin-3inliver[J].JHepatol,2011,54(5):975-983.JefticI,JovicicN,PanticJ,etal.Galectin-3AblationEnhancesLiverSteatosis,butAttenuatesInfltionandIL-33-DependentFibrosisinObesogenicMouseModelofNonalcoholicSteatohepatitis[J].MolMed,2015,21(1):453-465.HendersonNC,MackinnonAC,FarnworthSL,etal.Galectin-3regulatesmyofibroblastactivationandhepaticfibrosis[J].ProcNatlAcadSciUSA,2006,103(13):5060-5065.DonnellyKL,SmithCI,SchwarzenbergSJ,etal.Sourcesoffattyacidsstoredinliverandsecretedvialipoproteinsinpatientswithnonalcoholicfattyliverdisease[J].JClinInvest,2005,115(5):1343-1351.TorresDM,WilliamsCD,HarrisonSA.Features,diagnosis,andtreatmentofnonalcoholicfattyliverdisease[J].ClinGastroenterolHepatol,2012,10(8):837-858.ShimanoH,YahagiN,Amemiya-KudoM,etal.Sterolregulatoryelement-bindingprotein-1asatranscriptionfactorfornutritionalinductionoflipogenicenzymegenes[J].JBiolChem,CohenJC,HortonJD,HobbsHH.Humanfattyliverdisease:oldquestionsandnewinsights[J].Science,HardieDG.AMPK--sensingenergywhiletalkingtoothersignalingpathways[J].CellMetab,SchimmackG,DefronzoRA,MusiN.AMP-activatedproteinkinase:Roleinmetabolismandtherapeuticimplications[J].DiabetesObesMetab,2006,8(6):591-602.HardieDG.AMPK:akeyregulatorofenergybalanceinthesinglecellandthewholeorganism[J].IntJObes(Lond),2008,32(Suppl4):S7-S12.LiY,XuS,MihaylovaMM,etal.AMPKphosphorylatesandinhibitsSREBPactivitytoattenuatehepaticsteatosisandatherosclerosisindiet-inducedinsulin-resistantmice[J].CellMetab,2011,13(4):376-388.WangY,WuZ,LiD,etal.Involvementofoxygen-regulatedprotein150inAMP-activatedproteinkinase-mediatedalleviationoflipid-inducedendosmicreticulumstress[J].JBiolChem,FlammentM,KammounHL,HainaultI,etal.Endosmicreticulumstress:anewactorinthedevelopmentofhepaticsteatosis[J].CurrOpinLipidol,2010,21(3):239-246.BasseriS,AustinRC.ERstressandlipogenesis:aslipperyslopetowardhepaticsteatosis[J].DevCell,GentileCL,FryeMA,PagliassottiMJ.Fattyacidsandtheendosmicreticuluminnonalcoholicfattyliverdisease[J].Biofactors,2011,37(1):8-16.LeamyAK,EgnatchikRA,YoungJD.Molecularmechanismsandtheroleofsaturatedfattyacidsintheprogressionofnon-alcoholicfattyliverdisease[J