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 1998 Chymase AngIIformingenzymeinvitro Found clonedandcharacterizedbyDr HidenoriUrata Urata 1990 ACE Chymase Fe Ad Tian 1996 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 2005 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 Age 10months 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 Severalsi