1、1田小利人類群體遺傳室北京大學(xué)分子醫(yī)學(xué)研究所死亡代償期失代償期惡化期結(jié)構(gòu)和功能的改變-重塑高血壓，冠心病遺傳，心肌病瓣膜病，先心病*心力衰竭心力衰竭的誘因和病理過程2激素、藥物、神經(jīng)遞質(zhì)膜受體第二信使 Ca2+離子通道活性肽心力衰竭心律失常線粒體活性氧心臟病相關(guān)基因活性肽(1) (1) 心力衰竭心力衰竭可能的發(fā)展基礎(chǔ)3心力衰竭臨床診斷遺傳學(xué)通道電生理學(xué)神經(jīng)和信號轉(zhuǎn)導(dǎo)心肌重塑的關(guān)鍵分子細胞水平鑒定動物模型計算機數(shù)字化模擬3-D結(jié)構(gòu)研究作用機制及早期干預(yù)新藥靶點及可藥性早期診斷標記的可能性目前主要研究的內(nèi)容4AOGENReninACEANG I ANG II 5Salt/water balance

2、 Contraction of VSMC Mitogenic effects Neurotransmitter Hormone-stimulation factorCardiac output6PLDPLCAIIagbPCPADAGCholineIP3PIP2PKCMekMapkStatsERCa+ShcJaksSIEC-fosC-JunStatsSOSGrb2RasRafGTPC-mycEgrCa+Ca+Ca+Ca+7ReninAngiotensinogenACEAngiotensin IAngiotensin IIAT1AT2AngiotensinogenReninACEAT1AT210A

3、ngiotensinogenReninAngiotensin 1Angiotensin 2KininogenKallikreinBradykininInactive peptidesACERAS(AII/AT1)AS(a1)ETS(ET-1/ETA)1112Angiotensin 1BradykininAcSDKP(N-acetyl-Ser-Asp-Lys-Pro) Angiotensin IICell growth. etc.degraded fragmentsdegraded fragmentsActiate TGF- signalingACE (I/D)Earlier than 1994

4、: tends to associatedLater than 1994: tends to not associatedLVH of man, not womanDegree, not frequency of LVHACEI treatmentQT dispersion, heart rate variabilityExercise-induced LHV16AortaLungKidneyBrainLiverL. VentricleR. ventricleSk. musclerACEhACE17SDTGR5060708090100110-10-9-8,5-8-7,5506070809010

5、0110-10-9-8,5-8-7,5SDTGR302520151050SDTGRAII (pg/g)AI on coronary artery flowCardiac AII18ACEI1,61,82,02,22,42,62,83,0LV/BSD-shSD-abTGR-abTGR-shLV/B (mg/g)012345678ANFCol3%GAPDH020406080100120140160180SD-shTGR-shSD-abTGR-abSD-shTGR-shSD-abTGR-abANFCol3GAPDHSD-shSD-abTGR-abTGR-shSBP (mmHg)1921ACETGF-

6、TGF-R1Smad3Smad2Smad4ColTGF-GAPDHSmad3-pSmad3Smad2-pSmad2AcSDKPNTGRTGRL1172TGRL1173NTGRTGRL1172TGRL1173LisinoprilAcSDKPNTGRTGRL1172TGRL1173LisinoprilAcSDKP2223Transcriptional machineryCmGH-actEpigenetic modificationDefinition of CG island in RAS promoters24ATGTSS5-UTR1 kbCG sitesCTGTCCCTGGCTCCTTCCCT

7、GATCCCACCGCCAGCCTCACCCCACGGTTCCTCCATTGCCCCACCTCCCACTGCGCCGCCGGGCCTCTGCCAGGGTCAAGGGGCTTCCCCCCTCTGGCAGCAGACGCCATGGTGCCGAGGTGGCCTCCACAACCGCCCTGTGCGCCAATAGGACAAGACTGTCCTCCCTCCCCCACACTTGTCACTTTGAGGGACACGTGGATGAGACAGGAAAACACAGGGGAGTGTGGAGACCTGAGGTGACTTGGAGCAAGCCTCTCAACCTGAGCGGCAATTTCTTCATCTGTAAAATGAGGGGGT

8、TGTTCTCATCTCTGAGGCTTTGTGTCGCTCTCAAAGCCTGCTAGCCTCGGGTTCTAGGACTCTGTTGGGATCGTGTGTGATGTTTTCTGCTGAGCGACGGCAGCCTGTGTCCTCGGGGGGAAAGAGGGCAGGCGCTCCAAAGCTCCTGCGCTCTGTGGCTCCCCCTCCCTCGCAGCCCCAAGCCCCAGGTGTGCCGGCCGCCCTGAGCCCCTCCAGCACCTCCCGGAGGCGCCTGCAAGACACCTAAGGTCCCCGCCTCCCTCCTCTCCCCCCCGCCACACCCCTACCCCCGGCAGGCGA

9、CGTCCCCGCCCCTCGACCATGGCCTGGTGAAGAAGCCGGCCAGGCCCGATCAGCCCCATCCCCGCCGCACGAGCGGCGCCTGCGGACAGCTCCTGGGGCCCCGGCCTTGTCACTCCGGAGGCGGGAGGCTCCGGGGGGTCGGGCTGGGAAGATCGAGCCGGAGGCCGCTAGGCTCCCAGGCCCCGGCCGAGGCTGCGCGGCCGCACGGTGGGCAGGCTCGGGTGTTCCGGCAAACTGCCGGGTCCCCATCTTCAAAAGAGAGGAGGCCCTTTCTCCAGCTTCCTCTGCGGGAGCCCGACC

10、CAGCCCCATCCCGCCACCCCCGGGCTGCACCTCGGCCCCTCCCCGGCCCGCGCCCCTGCCCGGGGCGGGCCAGGAACCTCGGCCCGCGCCGCTGGGGACTTTGGAGCGGAGGAGGAAGCGCGGCGGGGCGGGGGCGGGGGTGTGTCGGGTTTTATAACCCGCAGGGCGGCCGCGGCGCAGGAGAAGGGGCAGAGCCGAGCACCGCGCACCGCGTCATGGGACE啟動子區(qū)CG島分析2526AngiotensinogenReninACEAT1aAT27469874588甲基化分析的原理27mCG 亞硫酸氫鈉mCG P

11、CR CG CG UG TG CN UN TN 克隆測序直接測序 Characteristics of ratsSHR/SP （N=20）WKY（N=20）P valueHR（bpm）376.834.6306.729.50.0000 SBP(mmHg)207.115.0130.610.30.0000 DBP(mmHg)164.814.995.211.90.0000 H/B(mg/g)4.160.013.690.0160.0000 V/B(mg/g)3.860.083.340.0170.0000 28CCG29100% protected = 100% methylationHow to quantify methylationCWKYSHR30Methylation of AOGCGCCCGCC31GCCCGCCCWKYSHRMethylation of ACE (reversal sequence)323334Met-?35Several signaling pathways are involved in the pa