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田小利 人类群体遗传室 北京大学分子医学研究所

田小利 人类群体遗传室 北京大学分子医学研究所. 心力衰竭的诱因和病理过程. 高血压，冠心病 遗传，心肌病 瓣膜病，先心病. *. 代偿期. 失代偿期. 恶化期. *. *. *. 死亡. 结构和功能的改变 --- 重塑. 心力衰竭. 心力衰竭可能的发展基础. 激素、药物、 神经递质. 活性肽. 膜受体. 离子通道. 活性肽. 第二信使 Ca 2+. (1). 心律失常. 心 力 衰 竭. 心力 衰竭. 心脏病相关基因. (1). 线粒体活性氧. 目前主要研究的内容. 心力衰竭. 临床诊断 遗传学 通道电生理学

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田小利 人类群体遗传室 北京大学分子医学研究所

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  1. 田小利 人类群体遗传室 北京大学分子医学研究所

  2. 心力衰竭的诱因和病理过程 高血压，冠心病 遗传，心肌病 瓣膜病，先心病 * 代偿期 失代偿期 恶化期 * * * 死亡 结构和功能的改变---重塑 心力衰竭

  3. 心力衰竭可能的发展基础 激素、药物、 神经递质 活性肽 膜受体 离子通道 活性肽 第二信使 Ca2+ (1) 心律失常 心 力 衰 竭 心力衰竭 心脏病相关基因 (1) 线粒体活性氧

  4. 目前主要研究的内容 心力衰竭 临床诊断 遗传学 通道电生理学 神经和信号转导 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 心肌重塑的关键分子

  5. AOGEN Renin ANG I ACE ANG II

  6. Salt/water balance Contraction of VSMC Mitogenic effects Neurotransmitter Hormone-stimulation factor Cardiac output

  7. AII b a g PLC PLD PIP2 PC Shc GTP PA Ras Choline IP3 DAG Grb2 SOS Raf PKC ++ Ca ++ ++ Ca Ca ++ Ca Mek ++ Ca ER Mapk Stats Stats SIE C-myc Jaks C-fos Egr C-Jun

  8. AOGEN Kallikrein Renin Capthepsin G Chymotrypsin ANG I Tonin Chymase Kallikrein ACE Capthesin G Chymotrypsin ANG II

  9. ANG1 perfusion isolated aorta 50 Chymase: 40 Nishimura, 1998 Ang II forming enzyme in vitro 30 %phenylephrine Found, cloned and characterized by Dr. Hidenori Urata 20 10 0 Captopril CV 11974 Cap + Aprot Chymostatin Cap + Chymo Fe Ad Chymase Tian, 1996 ACE Urata, 1990

  10. Angiotensinogen Renin ACE Angiotensinogen Renin AT1 Angiotensin I AT2 ACE Angiotensin II AT1 AT2

  11. Angiotensinogen Kininogen Renin Kallikrein Angiotensin 1 Bradykinin ACE Angiotensin 2 Inactive peptides AS RAS ETS (a1) (AII/AT1) (ET-1/ETA)

  12. Angiotensin 1 Angiotensin II Cell growth. etc. Bradykinin degraded fragments degraded fragments Actiate TGF-β signaling AcSDKP (N-acetyl-Ser-Asp-Lys-Pro)

  13. ACE ACE inhibitor NH2 Extracellular Clinical significance of this pathway is under investigation MKK7 Cytosol CK2 JNK COOH cJun JNK P P cJun P cJun P P cJun cJun P cJun P cJun Nucleus AP-1 Gene expression(ACE, COX-2) Fleming I et al. Physiology. 2005;20:91-5.

  14. Angiotensinogen (M235T) • Together with ACE-D, associated male LVH • CAD • AT1 (A1166C) • Associated male LVH

  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 LVH • ACEI treatment • QT dispersion, heart rate variability • Exercise-induced LHV

  16. le e cl ic scle ri tr nt ey en a . mu n g er ve rt dn V v Brai Lun Ao R. Sk Ki Li L. rAC E hA CE

  17. SD 110 TGR 100 90 30 80 25 70 60 20 50 15 -10 -9 -8,5 -8 -7,5 10 110 100 5 90 0 80 SD TGR 70 SD 60 TGR 50 -10 -9 -8,5 -8 -7,5 AII (pg/g) ACEI Cardiac AII AI on coronary artery flow

  18. 180 3,0 SD-sh 160 2,8 140 TGR-sh ) g / 120 SD-ab 2,6 g m 100 TGR-ab ( 2,4 80 B / 2,2 60 V L 40 2,0 20 1,8 0 b h b h 1,6 s a s a - - - - R R D D LV/B G G S S T T h s h - s R - 8 D G S S T 7 H 6 D P 5 A 4 G % 3 2 1 0 ANF Col3 ) g H m m ( P B S b b a a - - R D G SD-sh T TGR-sh ANF SD-ab TGR-ab Col3 GAPDH

  19. Age > 10 months TGRL1172 TGRL1173 Lisinopril AcSDKP NTGR col1 col3 GAPDH

  20. AcSDKP TGRL1172 TGRL1173 TGF-β NTGR TGF-β ACE TGF-R1 GAPDH TGRL1172 TGRL1173 Lisinopril AcSDKP NTGR Smad2-p Smad2 Smad3 Smad2 Smad4 TGRL1172 TGRL1173 Lisinopril AcSDKP NTGR Smad3-p Col Smad3

  21. Transcriptional machinery CmG H-act Epigenetic modification

  22. Definition of CG island in RAS promoters CG sites TSS 5-UTR ATG 1 kb

  23. ACE启动子区CG岛分析 CTGTCCCTGGCTCCTTCCCTGATCCCACCGCCAGCCTCACCCCACGGTTCCTCCATTGCC CCACCTCCCACTGCGCCGCCGGGCCTCTGCCAGGGTCAAGGGGCTTCCCCCCTCTGGCAG CAGACGCCATGGTGCCGAGGTGGCCTCCACAACCGCCCTGTGCGCCAATAGGACAAGACT GTCCTCCCTCCCCCACACTTGTCACTTTGAGGGACACGTGGATGAGACAGGAAAACACAG GGGAGTGTGGAGACCTGAGGTGACTTGGAGCAAGCCTCTCAACCTGAGCGGCAATTTCTT CATCTGTAAAATGAGGGGGTTGTTCTCATCTCTGAGGCTTTGTGTCGCTCTCAAAGCCTG CTAGCCTCGGGTTCTAGGACTCTGTTGGGATCGTGTGTGATGTTTTCTGCTGAGCGACGG CAGCCTGTGTCCTCGGGGGGAAAGAGGGCAGGCGCTCCAAAGCTCCTGCGCTCTGTGGCT CCCCCTCCCTCGCAGCCCCAAGCCCCAGGTGTGCCGGCCGCCCTGAGCCCCTCCAGCACC TCCCGGAGGCGCCTGCAAGACACCTAAGGTCCCCGCCTCCCTCCTCTCCCCCCCGCCACA CCCCTACCCCCGGCAGGCGACGTCCCCGCCCCTCGACCATGGCCTGGTGAAGAAGCCGGC CAGGCCCGATCAGCCCCATCCCCGCCGCACGAGCGGCGCCTGCGGACAGCTCCTGGGGCC CCGGCCTTGTCACTCCGGAGGCGGGAGGCTCCGGGGGGTCGGGCTGGGAAGATCGAGCCG GAGGCCGCTAGGCTCCCAGGCCCCGGCCGAGGCTGCGCGGCCGCACGGTGGGCAGGCTCG GGTGTTCCGGCAAACTGCCGGGTCCCCATCTTCAAAAGAGAGGAGGCCCTTTCTCCAGCT TCCTCTGCGGGAGCCCGACCCAGCCCCATCCCGCCACCCCCGGGCTGCACCTCGGCCCCT CCCCGGCCCGCGCCCCTGCCCGGGGCGGGCCAGGAACCTCGGCCCGCGCCGCTGGGGACT TTGGAGCGGAGGAGGAAGCGCGGCGGGGCGGGGGCGGGGGTGTGTCGGGTTTTATAACCC GCAGGGCGGCCGCGGCGCAGGAGAAGGGGCAGAGCCGAGCACCGCGCACCGCGTCATGGG

  24. Angiotensinogen Renin ACE AT1a AT2 74 69 87 45 88

  25. 甲基化分析的原理 亚硫酸氢钠 CG UG TG 克隆测序 PCR mCG mCG CG 直接测序 CN UN TN

  26. Characteristics of rats

  27. How to quantify methylation C C CG 100% protected = 100% methylation

  28. Methylation of AOG CC CG CC CG SHR WKY

  29. Methylation of ACE (reversal sequence) CC GC CC GC SHR WKY

  30. Met --- ? ? ?

  31. 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

  32. 谢谢

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