心力衰竭的信号通路,,.ppt

1,田小利人类群体遗传室北京大学分子医学研究所,死亡,代偿期,失代偿期,恶化期,结构和功能的改变-重塑,高血压，冠心病遗传，心肌病瓣膜病，先心病,*,*,*,*,心力衰竭,心力衰竭的诱因和病理过程,2,激素、药物、神经递质,膜受体,第二信使Ca2+,离子通道,活性肽,心力衰竭,心律失常,线粒体活性氧,心脏病相关基因,活性肽,(1),(1),心力衰竭,心力衰竭可能的发展基础,3,心力衰竭,临床诊断遗传学通道电生理学神经和信号转导,心肌重塑的关键分子,细胞水平鉴定动物模型计算机数字化模拟3-D结构研究,作用机制及早期干预新药靶点及可药性早期诊断标记的可能性,目前主要研究的内容,4,AOGEN,Renin,ACE,ANGI,ANGII,5,Salt/waterbalance,ContractionofVSMC,Mitogeniceffects,Neurotransmitter,Hormone-stimulationfactor,Cardiacoutput,6,PLD,PLC,AII,a,g,b,PC,PA,DAG,Choline,IP3,PIP2,PKC,Mek,Mapk,Stats,ER,Ca,+,Shc,Jaks,SIE,C-fos,C-Jun,Stats,SOS,Grb2,Ras,Raf,GTP,C-myc,Egr,Ca,+,Ca,+,Ca,+,Ca,+,7,AOGEN,Renin,ACE,ANGI,ANGII,8,9,50,40,30,20,10,0,Captopril,Chymostatin,Cap+Chymo,Cap+Aprot,CV11974,%phenylephrine,ANG1perfusionisolatedaorta,Nishimura,2019,Chymase:,AngIIformingenzymeinvitro,Found,clonedandcharacterizedbyDr.HidenoriUrata,Urata,1990,ACE,Chymase,Fe,Ad,Tian,2019,Renin,Angiotensinogen,ACE,AngiotensinI,AngiotensinII,AT1,AT2,AT1,AT2,10,Angiotensinogen,Renin,Angiotensin1,Angiotensin2,Kininogen,Kallikrein,Bradykinin,Inactivepeptides,ACE,RAS,(AII/AT1),AS,(a1),ETS,(ET-1/ETA),11,12,Angiotensin1,Bradykinin,AcSDKP(N-acetyl-Ser-Asp-Lys-Pro),AngiotensinIICellgrowth.etc.,degradedfragments,degradedfragmentsActiateTGF-signaling,13,FlemingIetal.Physiology.2019;20:91-5.,ACE,NH2,ACEinhibitor,Extracellular,Cytosol,COOH,Nucleus,Geneexpression(ACE,COX-2),CK2,JNK,MKK7,P,JNK,cJun,cJun,P,cJun,P,cJun,P,cJun,P,AP-1,cJun,P,cJun,P,Clinicalsignificanceofthispathwayisunderinvestigation,Angiotensinogen(M235T)TogetherwithACE-D,associatedmaleLVHCAD,AT1(A1166C)AssociatedmaleLVH,14,15,ACE(I/D)Earlierthan1994:tendstoassociatedLaterthan1994:tendstonotassociatedLVHofman,notwomanDegree,notfrequencyofLVHACEItreatmentQTdispersion,heartratevariabilityExercise-inducedLHV,16,Ao,rt,a,Lun,g,Ki,dn,ey,Brai,n,Li,v,er,L.,V,en,tr,ic,le,R.,ve,nt,ri,cl,e,Sk,.mu,scle,rAC,E,hA,CE,17,AII(pg/g),AIoncoronaryarteryflow,CardiacAII,18,ACEI,19,20,Age10months,col1,col3,GAPDH,NTGR,TGRL1172,TGRL1173,Lisinopril,AcSDKP,21,ACE,TGF-,TGF-R1,Smad3,Smad2,Smad4,Col,TGF-,GAPDH,Smad3-p,Smad3,Smad2-p,Smad2,AcSDKP,NTGR,TGRL1172,TGRL1173,NTGR,TGRL1172,TGRL1173,Lisinopril,AcSDKP,NTGR,TGRL1172,TGRL1173,Lisinopril,AcSDKP,22,23,DefinitionofCGislandinRASpromoters,24,ATG,TSS,5-UTR,1kb,CGsites,CTGTCCCTGGCTCCTTCCCTGATCCCACCGCCAGCCTCACCCCACGGTTCCTCCATTGCCCCACCTCCCACTGCGCCGCCGGGCCTCTGCCAGGGTCAAGGGGCTTCCCCCCTCTGGCAGCAGACGCCATGGTGCCGAGGTGGCCTCCACAACCGCCCTGTGCGCCAATAGGACAAGACTGTCCTCCCTCCCCCACACTTGTCACTTTGAGGGACACGTGGATGAGACAGGAAAACACAGGGGAGTGTGGAGACCTGAGGTGACTTGGAGCAAGCCTCTCAACCTGAGCGGCAATTTCTTCATCTGTAAAATGAGGGGGTTGTTCTCATCTCTGAGGCTTTGTGTCGCTCTCAAAGCCTGCTAGCCTCGGGTTCTAGGACTCTGTTGGGATCGTGTGTGATGTTTTCTGCTGAGCGACGGCAGCCTGTGTCCTCGGGGGGAAAGAGGGCAGGCGCTCCAAAGCTCCTGCGCTCTGTGGCTCCCCCTCCCTCGCAGCCCCAAGCCCCAGGTGTGCCGGCCGCCCTGAGCCCCTCCAGCACCTCCCGGAGGCGCCTGCAAGACACCTAAGGTCCCCGCCTCCCTCCTCTCCCCCCCGCCACACCCCTACCCCCGGCAGGCGACGTCCCCGCCCCTCGACCATGGCCTGGTGAAGAAGCCGGCCAGGCCCGATCAGCCCCATCCCCGCCGCACGAGCGGCGCCTGCGGACAGCTCCTGGGGCCCCGGCCTTGTCACTCCGGAGGCGGGAGGCTCCGGGGGGTCGGGCTGGGAAGATCGAGCCGGAGGCCGCTAGGCTCCCAGGCCCCGGCCGAGGCTGCGCGGCCGCACGGTGGGCAGGCTCGGGTGTTCCGGCAAACTGCCGGGTCCCCATCTTCAAAAGAGAGGAGGCCCTTTCTCCAGCTTCCTCTGCGGGAGCCCGACCCAGCCCCATCCCGCCACCCCCGGGCTGCACCTCGGCCCCTCCCCGGCCCGCGCCCCTGCCCGGGGCGGGCCAGGAACCTCGGCCCGCGCCGCTGGGGACTTTGGAGCGGAGGAGGAAGCGCGGCGGGGCGGGGGCGGGGGTGTGTCGGGTTTTATAACCCGCAGGGCGGCCGCGGCGCAGGAGAAGGGGCAGAGCCGAGCACCGCGCACCGCGTCATGGG,ACE启动子区CG岛分析,25,26,AngiotensinogenReninACEAT1aAT2,7469874588,甲基化分析的原理,27,mCG,亚硫酸氢钠,mCG,PCR,CG,CG,UG,TG,CN,UN,TN,克隆测序,直接测序,Characteristicsofrats,28,C,CG,29,100%protected=100%methylation,Howtoquantifymethylation,C,WKY,SHR,30,MethylationofAOG,CG,CC,CG,CC,31,GC,CC,GC,CC,WKY,SHR,MethylationofACE(reversalsequence),32,33,34,Met,-,?,?,?,35,Severals