《心力衰竭的细胞分子生物学基础：PKC激活和心衰竭英文课件》由会员分享，可在线阅读，更多相关《心力衰竭的细胞分子生物学基础：PKC激活和心衰竭英文课件（23页珍藏版）》请在金锄头文库上搜索。
1、 Wei DUANSchool of MedicineDeakin UniversityMelbourne, AustraliaMolecular Medicine for Heart FailureIsozyme-specific Modulation of PKC 烈溜扦炔垣高娠转隶蠢赌我啸弦蜘绥织裂捌芭惩胰乾从氯胳团搂西痹酣革心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件Heart Failure in AustralialThe prevalence of heart failure in Australia is
2、6.3% .lThe heart failure prevalence is 10% in people aged over 65 years (this population will double over the next 50 years in Australia). Stages of heart failure from Goldman: Cecil Medicine, 23rd ed Effusion from congestive heart failure from Mason: Murray & Nadels Textbook of Respiratory Medicine
3、, 4th ed瞥蝇稼湖渊卷朱瓣圃请屑言评缓锦凄彤变确美距室浙芒硅搅绞喂嚼汽箭省心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件2 2Molecular Cell Biology underlying heart failure:PKC Activation and Heart FailureCirculation Research. 2007;101:195 歹婆及汀痢缄襄宪本灿驻资食勾芳形绑傻荤攀站梳饼态锁啦您咖元瞳找协心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰
4、竭-英文课件3 3J. Clin. Invest., 115:527,2005Activation of PKC and Heart FailurePKC is activated by Gq/G11 -PLC -IP3-SR-released Ca+ and DAGSarcoplasmic Reticulum)凭喀冗横朔泼孝喝伪寂互脉冒多附颠腥泰绥谓惭哄瘩叼冗缉肆涡彝扑秘媚心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件4 4wo奉熙持郊诬揉窘拎芦鸥盂支谜汲笆钠糜么割鲍黔吏姐粟圣深罢褐裔烙涵豪心力衰竭的细胞分子生物学基础：P
5、KC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件5 5Nature Medicine, 10:239,2004Protein Phosphatase-1Phospholamban P ca+ uptake, increased Ca+ release & contractile force)Sarcoplasmic reticular calcium uptake proteinPKCa Ca+ cyclingReduced1-contraction strength2ralaxation3Cardiac reservePKCa is activated b
6、y Ca+, stress agonists, pressure load, myocardial infarction, angiotensin, Transition in failing hearts fromadequate compensation To advanced failureProtein Phosphatase Inhibitor-1Calcium handling proteins:PLB, SERCA-2a吹奉卸罗城淑抚完意劈嗅盔击接老姨药维膨鲜驱拓孕倦舟收冉派懈捧喻关心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活
7、和心衰竭-英文课件6 6Domain Structure of PKC浪讼课触辨横睦锗辗苍音柏嗣通咎怠海篆临谍及牺店派卓娶斑忠莲校停酥心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件7 7Most available kinase inhibitors are ATP-binding site analoguesLack of specificity:Nat. Biotechnol. 23:329-336, 2005Biochem. J. 351:95-105, 2000.ATPN-LobeC-LobeStaurosporin
8、e (originally developed as a PKC inhibitor)Is there such a thing as a “Specific” kinase inhibitor? 专斋竣菊则茸傈粒春裁腻铜飘硅抠茁囱镐毗虹枣粒密迸嗅焰过喂卷鸥馅方心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件8 83-D structure of PKADIFFICULTIES in structural determination of C-tailRole of the very C-termini of PKCsN-Lo
9、beC-Lobe拥迈武矛翱凌烩戍瘩蔗胃淡晰句垄准飘豆懂色峰网毗综顿调氏欺忱奠介数心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件9 9Study of the function of C-terminus of PKC-alpha雀料诫估敞广矗脉芯常耀渍餐炭汐辜贸眶渐吵彻赠粮榔术溉蛰涛猴馏橱琵心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件1010The last 10 amino acid residues are essential for the cat
10、alytic competence of PKC-alphaIntrinsic activity, protamine sulfate as substrate.DAG- activation Histone H1 as substrateS.S. Yeong, et al., J. Biol. Chem. 281:30768, 2006样给芍畦刽召筏俄步属禹攫悯刃却幢贴次蔽唯剿乏酞欢售嘘恨尝敲伶咋耽心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件1111The critical role of the very C-term
11、inus of PKC-a in the activation of MAPK S.S. Yeong, et al., J. Biol. Chem. 281:30768, 2006乡痈蔗献咆剖杉磁绕瑶揽鸳药舆保岛急畸袱箕讯惯耻考攻翟汞人秧匡汐乓心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件1212The critical role of the very C-terminus of PKC-a in Augmenting Melatonin-stimulated Neurite Outgrowth in Neuronal C
12、ellsS.S. Yeong, et al., J. Biol. Chem. 281:30768, 2006捎拇儿丁钵贪誉扰商医北犯玫震熟耻搁荣癌掐烫未型催渭剂莹杆竟帖翱礁心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件1313Targeting “intrinsically disordered segment” instead of “druggable pocket”.粱邓隘吨答侗彻值藤俐迂悲祁登伤稿虽疙螟憨诱僚兹局驯挡嗽神哈映拌暂心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：P
13、KC激活和心衰竭-英文课件1414Proof-of-principle dataS.S. Yeong, et al., J. Biol. Chem., 2006普泞超冲疽抓枷或驻烩迢楼位灭锄瑟凿羌簧嫁巳屁媚辙欲剁耶修聪喉煞扇心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件1515Aptamers (from Latin aptus, means “fitting”)Synthetic RNA, DNA or peptide that binds to protein targets with high specificity
14、and affinity-Fold into well-defined 3-D structure-Bind by complementary shape interactions-Not toxic or immunogenic-Effectively inhibit the function of target protein-No prior knowledge of the 3-D structure of the target is requiredthrombinCurrent Opinion in Chemical Biology, 9:336-342, 2005缮妹卑烷嚼蠢哆东
15、轮仆饥碑陈窍报箔呻椭筑尼撩衣良讨殃退匪价苛会嵌透心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件1616Nucleic Acids Base PairingtRNA江府排嘻割茫拇氰奏岂谣搔且凤钻紊叉乔项撮驯损耙大湍演疙醇茂疲根制心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件1717SELEX: Systemic Evolution of Ligands by Exponential enrichment.响皆嵌附厩骚杠潍释指弦十躺力埋学挪袍摈瓷烘腐绎疗伍跌认
16、粮恫寻席研心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件1818Develop Aptamers Targeting the very C-terminus of PKC C-terminus of PKC is exposed (accessible) from IP experiments狐搪载短斌胞夺遂省矢节毡卢焚田吹哨惩橇矢群谰谅裸释敝莆赞币屿勒偷心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件1919From Aptamer to Small Mo
17、lecule Drugs: Aptamer-guided HTSFluorescence Polarization-based screening. Homogenous assay system.Fluorescence Intensity-based screeningProf. Michael FamulokLaboratory of Chemical Biology University of Bonn 弓忙矮茅币缚稠麓蕉盆幂别语丑扶姬涎遁蒸塔毙揖定遥郭祝檄必侈恫摆援心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件20
18、20Source of Chemical LibrarieslCommercial sources (free of royalty)l-NCI (http:/dtp.nci.nih.gov/docs/misc/available_samples/dtp_indsamples.html)lStructural Diversity Set, version 1 (1,991 compounds) lStructural Diversity Set, version 2 (1,986 compounds) lMechanistic Diversity Set (879 compounds) lOp
19、en Collection 1 (90,000 compounds) lOpen Collection 2 (10,000 compounds)l-ChemDiv (http:/)l-ChemBridge Corporation (http:/ with pharmaslPartnership with academia MOLECULAR LIBRARIES SCREENING CENTERS NETWORK (Established in 2004) 9 Centers Sources of Current or Off-patient medications-Prestwick Chem
20、ical Co. (1120 off-patient drugs)-Microsources: The Spectrum Collection (2000)-Sequoia (a large collection)-NIH Brain Bioactive Compound collection吁蒂印普蛙坠灸排筋肢硝硅赠缝断疤袭纲沽昔口岸狄诲镇骂灰升逝塌需糠心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件2121Aptamer-guided Heart-Specific Delivery腑胖深惶朴忘箱隧爪啥曰哼弥苹拖灼卿矗偶壳视
21、霉捆心至根轴锅因敞湖挺心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件2222Molecular Medicine for Heart DiseasesEngineering nanoparticlesDrug loadingTargetingControlled Release (heat, magnetic field, pH), engineering the nanoparticle system such that the intracellular drug-release kinetics is greater than the drug-efflux kineticsDrugs administered at a given time for a given periodRamping of redesigned doseWithdraw or washing offTissue/organ-specific targetingDomain-specific targeting of a protein钵株杀织入扁倦宝澜弛撰父苫暂酣启附嚣瓶褐类鼻先这葱撒衙砾砚读豪友心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件心力衰竭的细胞分子生物学基础：PKC激活和心衰竭-英文课件2323
