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1、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
2、主要研究的内容,4,AOGEN,Renin,ACE,ANG I,ANG II,5,Salt/water balance,Contraction of VSMC,Mitogenic effects,Neurotransmitter,Hormone-stimulation factor,Cardiac output,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
3、,+,Ca,+,Ca,+,7,AOGEN,Renin,ACE,ANG I,ANG II,8,9,50,40,30,20,10,0,Captopril,Chymostatin,Cap + Chymo,Cap + Aprot,CV 11974,%phenylephrine,ANG1 perfusion isolated aorta,Nishimura, 1998,Chymase:,Ang II forming enzyme in vitro,Found, cloned and characterized by Dr. Hidenori Urata,Urata, 1990,ACE,Chymase,F
4、e,Ad,Tian, 1996,Renin,Angiotensinogen,ACE,Angiotensin I,Angiotensin II,AT1,AT2,AT1,AT2,10,Angiotensinogen,Renin,Angiotensin 1,Angiotensin 2,Kininogen,Kallikrein,Bradykinin,Inactive peptides,ACE,RAS,(AII/AT1),AS,(a1),ETS,(ET-1/ETA),11,12,Angiotensin 1,Bradykinin,AcSDKP (N-acetyl-Ser-Asp-Lys-Pro),Angi
5、otensin II Cell growth. etc.,degraded fragments,degraded fragments Actiate TGF- signaling,13,Fleming I et al. Physiology. 2005;20:91-5.,ACE,NH2,ACE inhibitor,Extracellular,Cytosol,COOH,Nucleus,Gene expression (ACE, COX-2),CK2,JNK,MKK7,P,JNK,cJun,cJun,P,cJun,P,cJun,P,cJun,P,AP-1,cJun,P,cJun,P,Clinica
6、l significance of this pathway is under investigation,Angiotensinogen (M235T) Together with ACE-D, associated male LVH CAD,AT1 (A1166C) Associated male LVH,14,15,ACE (I/D) Earlier than 1994: tends to associated Later than 1994: tends to not associated LVH of man, not woman Degree, not frequency of L
7、VH ACEI treatment QT dispersion, heart rate variability Exercise-induced LHV,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),AI on coronary artery flow,Cardiac AII,18,ACEI,19,20,Age 10 months,col1,col3,GAPDH,NTGR,TGRL1172,TGRL1173,Lis
8、inopril,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,Definition of CG island in RAS promoters,24,ATG,TSS,5-UTR,1 kb,CG sites,CTGTCCCTGGCTCCT
9、TCCCTGATCCCACCGCCAGCCTCACCCCACGGTTCCTCCATTGCC CCACCTCCCACTGCGCCGCCGGGCCTCTGCCAGGGTCAAGGGGCTTCCCCCCTCTGGCAG CAGACGCCATGGTGCCGAGGTGGCCTCCACAACCGCCCTGTGCGCCAATAGGACAAGACT GTCCTCCCTCCCCCACACTTGTCACTTTGAGGGACACGTGGATGAGACAGGAAAACACAG GGGAGTGTGGAGACCTGAGGTGACTTGGAGCAAGCCTCTCAACCTGAGCGGCAATTTCTT CATCTGTAAA
10、ATGAGGGGGTTGTTCTCATCTCTGAGGCTTTGTGTCGCTCTCAAAGCCTG CTAGCCTCGGGTTCTAGGACTCTGTTGGGATCGTGTGTGATGTTTTCTGCTGAGCGACGG CAGCCTGTGTCCTCGGGGGGAAAGAGGGCAGGCGCTCCAAAGCTCCTGCGCTCTGTGGCT CCCCCTCCCTCGCAGCCCCAAGCCCCAGGTGTGCCGGCCGCCCTGAGCCCCTCCAGCACC TCCCGGAGGCGCCTGCAAGACACCTAAGGTCCCCGCCTCCCTCCTCTCCCCCCCGCCACA CCCCT
11、ACCCCCGGCAGGCGACGTCCCCGCCCCTCGACCATGGCCTGGTGAAGAAGCCGGC CAGGCCCGATCAGCCCCATCCCCGCCGCACGAGCGGCGCCTGCGGACAGCTCCTGGGGCC CCGGCCTTGTCACTCCGGAGGCGGGAGGCTCCGGGGGGTCGGGCTGGGAAGATCGAGCCG GAGGCCGCTAGGCTCCCAGGCCCCGGCCGAGGCTGCGCGGCCGCACGGTGGGCAGGCTCG GGTGTTCCGGCAAACTGCCGGGTCCCCATCTTCAAAAGAGAGGAGGCCCTTTCTCCAGCT
12、TCCTCTGCGGGAGCCCGACCCAGCCCCATCCCGCCACCCCCGGGCTGCACCTCGGCCCCT CCCCGGCCCGCGCCCCTGCCCGGGGCGGGCCAGGAACCTCGGCCCGCGCCGCTGGGGACT TTGGAGCGGAGGAGGAAGCGCGGCGGGGCGGGGGCGGGGGTGTGTCGGGTTTTATAACCC GCAGGGCGGCCGCGGCGCAGGAGAAGGGGCAGAGCCGAGCACCGCGCACCGCGTCATGGG,ACE启动子区CG岛分析,25,26,Angiotensinogen Renin ACE AT1a AT2,74
13、 69 87 45 88,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,Characteristics of rats,28,C,CG,29,100% protected = 100% methylation,How to quantify methylation,C,WKY,SHR,30,Methylation of AOG,CG,CC,CG,CC,31,GC,CC,GC,CC,WKY,SHR,Methylation of ACE (reversal sequence),32,33,34,Met,-,?,?,?,35,Several signaling pathways are involved in the pathogenesis of heart failure RAS plays a role in cardiac dysfunction through multiple pathways Expression and epigenetic modifications of RAS plays a critical roles in heart failure,36,谢谢,