脉络膜新生血管阶段PPT课件

.,1,脉络膜新生血管CNV,.,2,CNV的发生机制,RPE-Bruch膜-脉络膜毛细血管复合体改变对CNV的影响,.,3,.,4,C57BL/6J（B6）Laser-inducedCNV,腹腔麻醉：0.5%戊巴比妥钠散瞳：托品酰胺苯肾上腺素激光：647.1nm;50mmspotsize;0.05sduration;360mW.1PD；3,6,9,12oclockpositions,.,5,Fundusfluoresceinangiography,3minafterintraperitonealinjectionof0.3mLof2%fluoresceinsodiumwasinjectedintotheintraperitonealcavityofthemice.,.,6,细胞,.,7,新生血管形成过程,内皮细胞的活化（缺氧）(HIF-1)VEGFNO(血管舒张);内皮细胞通透性增加，有利于血浆向组织扩散血管外基质的降解内皮细胞的增生、移行新生血管的成熟,VEGF,bFGF,T-PA,u-PA,TNF-a,IL-1,MMP-1,MMP-3,上调,VEGF,NOcGMP,MAPK,bFGF,整合素avB3等,PDGF,aFGF,Ang及受体Tie-1,Tie-2,.,8,RPE对CNV的双重调节功能,1.促进作用生成促进血管内皮细胞增生和移行的VEGF,FGF,TGF-a,TNF-a等等诱导体内血管内皮细胞形成窗孔结构，影响新生血管的成熟2.抑制作用直接接触抑制血管内皮细胞的移行分泌抑制血管内皮细胞生长的物质：TGF-b,PEDF释放凝血酶原激活物抑制因子，使纤维酶原向纤溶酶的转化受阻，细胞外基质不能降解,.,9,巨噬细胞,激光诱导CNV，第一天巨噬细胞出现，第三天达到高峰，5-7天后开始减少。,VEGF，MMP-9蛋白水解酶（玻璃膜）,IL-1a,IL-1b,TNF-aIL-8,MCP-1,生成血管活性因子,巨噬细胞+RPE,.,10,参与血管内皮生长因子诱发脉络膜新生血管的信号通路,MAPK途径PI-3K-AKt/PKB途径钙离子依赖性激酶途径NO途径,.,11,P38内皮细胞移行,VEGF诱导活化:ERK,JNK,.,12,PI-3K:CEC增生,ILK：内皮细胞增生和移行,.,13,.,14,.,15,转录因子,STAT3NF-kappa-BHIF-1,.,16,STAT3,Signaltransducerandtranscriptionactivator退化期CNV的RPE细胞中，有STAT3的高表达，而在已纤维化的盘状瘢痕中，STAT3的表达呈阴性，提示STAT3的活化与CNV的纤维化有关。,.,17,STAT3+CNV,1.AnovelprotectiverolefortheinnateimmunityToll-LikeReceptor3(TLR3)intheretinaviaStat3.MolCellNeurosci.2014Sep28;63C:38-48IF:3.732.CNTF-mediatedprotectionofphotoreceptorsrequiresinitialactivationofthecytokinereceptorgp130inMllerglialcells.ProcNatlAcadSciUSA.2013Nov19;110(47):E4520-9IF:9.813.Toll-likereceptor3(TLR3)protectsretinalpigmentedepithelium(RPE)cellsfromoxidativestressthroughaSTAT3-dependentmechanism.MolImmunol.2013Jun;54(2):122-31IF:3.04.SuppressionofchoroidalneovascularizationthroughinhibitionofAPE1/Ref-1redoxactivity.InvestOphthalmolVisSci.2014Jun26;55(7):4461-9IF.3.665.IL-27inhibitspathophysiologicalintraocularneovascularizationduetolaserburn.JLeukocBiol.2012Feb;91(2):267-73IF:4.36.Interleukin-6receptor-mediatedactivationofsignaltransducerandactivatoroftranscription-3(STAT3)promoteschoroidalneovascularization.AmJPathol.2007Jun;170(6):2149-58IF:4.67.Hyperglycaemiaexacerbateschoroidalneovascularisationinmiceviatheoxidativestress-inducedactivationofSTAT3signallinginRPEcells.PLoSOne.2012;7(10):e47600.doi:10.1371/journal.pone.0047600.Epub2012Oct19,.,18,NF-kappa-B,NFKBisatranscriptionregulatorthatisactivatedbyvariousintra-andextra-cellularstimulisuchascytokines,oxidant-freeradicals,ultravioletirradiation,andbacterialorviralproducts.ActivatedNFKBtranslocatesintothenucleusandstimulatestheexpressionofgenesinvolvedinawidevarietyofbiologicalfunctions.InappropriateactivationofNFKBhasbeenassociatedwithanumberofinflammatorydiseaseswhilepersistentinhibitionofNFKBleadstoinappropriateimmunecelldevelopmentordelayedcellgrowth.NFB受多种细胞内和细胞外的刺激如细胞因子，氧化剂自由基，紫外线照射，细菌性或病毒性产物激活的转录调节子。激活的NFB易位到细胞核中，并刺激参与多种生物功能的基因的表达。NFB的不适当活化已经与许多炎症性疾病相关，而NFKB的持久性抑制导致不适当的免疫细胞的发育或延缓细胞生长。,.,19,NF-kappa-B,1.Rolesfortheubiquitin-proteasomepathwayinproteinqualitycontrolandsignalingintheretina:implicationsinthepathogenesisofage-relatedmaculardegeneration.MolAspectsMed.2012Aug;33(4):446-66IF:10.32.Macularpigmentluteinisantiinflammatoryinpreventingchoroidalneovascularization.ArteriosclerThrombVascBiol.2007Dec;27(12):2555-62IF:5.533.IKK2inhibitionattenuateslaser-inducedchoroidalneovascularization.PLoSOne.2014;9(1):e87530IF:3.534.TNF-decreasesVEGFsecretioninhighlypolarizedRPEcellsbutincreasesitinnon-polarizedRPEcellsrelatedtocrosstalkbetweenJNKandNF-Bpathways.PLoSOne.2013;8(7):e69994IF:3.535.NLRP3inflammasomeactivationinretinalpigmentepithelialcellsbylysosomaldestabilization:implicationsforage-relatedmaculardegeneration.InvestOphthalmolVisSci.2013Jan7;54(1):110-20IF:3.666.RegulatoryroleofHIF-1alphainthepathogenesisofage-relatedmaculardegeneration(AMD).AgeingResRev.2009Oct;8(4):349-58IF:7.637.RolesofNFB-miR-29s-MMP-2circuitryinexperimentalchoroidalneovascularization.JNeuroinflammation.2014May15;11:88IF:4.9,.,20,HIF-1,Functionsasamastertranscriptionalregulatoroftheadaptiveresponsetohypoxia.Underhypoxicconditions,activatesthetranscriptionofover40genes,includingerythropoietin,glucosetransporters,glycolyticenzymes,vascularendothelialgrowthfactor,HILPDA,andothergeneswhoseproteinproductsincreaseoxygendeliveryorfacilitatemetabolicadaptationtohypoxia.Playsanessentialroleinembryonicvascularization,tumorangiogenesisandpathophysiologyofischemicdisease.缺氧适应性反应的主转录调节。在缺氧条件下，激活了40个基因，包括促红细胞生成素，葡萄糖转运，糖酵解酶，血管内皮生长因子，乳过氧化物酶，和其他基因，其蛋白产物增加氧气传递或促进代谢适应低氧的转录。在胚胎血管生成，肿瘤血管生成和缺血性疾病的病理生理学中起重要作用。,.,21,HIF-1,1.Decorininhibitsangiogenicpotentialofchoroid-retinalendothelialcellsbydownregulatinghypoxia-inducedMet,Rac1,HIF-1andVEGFexpressionincoculturedretinalpigmentepithelialcells.ExpEyeRes.2013Nov;116:151-60IF:3.022.Methallothionein-3contributestovascularendothelialgrowthfactorinductioninamousemodelofchoroidalneovascularization.Metallomics.2013Oct;5(10):1387-96IF:3.983.Impactsofhypoxia-induciblefactor-1knockoutintheretinalpigmentepitheliumonchoroidalneovascularization.InvestOphthalmolVisSci.2012Sep14;53(10):6197-206IF:3.664.InfluenceofDll4viaHIF-1-VEGFsignalingontheangiogenesisofchoroidalneovascularizationunderhypoxi