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

1、 wei duanschool of medicinedeakin universitymelbourne, australiamolecular medicine for heart failureisozyme-specific modulation of pkc heart failure in australialthe prevalence of heart failure in australia is 6.3% .lthe heart failure prevalence is 10% in people aged over 65 years (this population w

2、ill 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, 4th edmolecular cell biology underlying heart failure:pkc activation and heart failu

3、recirculation research. 2007;101:195 j. clin. invest., 115:527,2005activation of pkc and heart failurepkc is activated by gq/g11 -plc -ip3-sr-released ca+ and dagsarcoplasmic reticulum)wonature medicine, 10:239,2004protein phosphatase-1phospholamban p ca+ uptake, increased ca+ release & contract

4、ile force)sarcoplasmic reticular calcium uptake proteinpkca ca+ cyclingreduced1-contraction strength2ralaxation3cardiac reservepkca is activated by ca+, stress agonists, pressure load, myocardial infarction, angiotensin, transition in failing hearts fromadequate compensation to advanced failureprote

5、in phosphatase inhibitor-1calcium handling proteins:plb, serca-2adomain structure of pkcmost available kinase inhibitors are atp-binding site analogueslack of specificity:nat. biotechnol. 23:329-336, 2005biochem. j. 351:95-105, 2000.atpn-lobec-lobestaurosporine (originally developed as a pkc inhibit

6、or)is there such a thing as a “specific” kinase inhibitor? 3-d structure of pkadifficulties in structural determination of c-tailrole of the very c-termini of pkcsn-lobec-lobestudy of the function of c-terminus of pkc-alphathe last 10 amino acid residues are essential for the catalytic competence of

7、 pkc-alphaintrinsic activity, protamine sulfate as substrate.dag- activation histone h1 as substrates.s. yeong, et al., j. biol. chem. 281:30768, 2006the critical role of the very c-terminus of pkc-a in the activation of mapks.s. yeong, et al., j. biol. chem. 281:30768, 2006the critical role of the

8、very c-terminus of pkc-a in augmenting melatonin-stimulated neurite outgrowth in neuronal cellss.s. yeong, et al., j. biol. chem. 281:30768, 2006targeting “intrinsically disordered segment” instead of “druggable pocket”.proof-of-principle datas.s. yeong, et al., j. biol. chem., 2006aptamers (from la

9、tin aptus, means “fitting”)synthetic rna, dna or peptide that binds to protein targets with high specificity 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 th

10、e 3-d structure of the target is requiredthrombincurrent opinion in chemical biology, 9:336-342, 2005trnaselex: systemic evolution of ligands by exponential enrichment.develop aptamers targeting the very c-terminus of pkc c-terminus of pkc is exposed (accessible) from ip experimentsfrom aptamer to s

11、mall molecule drugs: aptamer-guided htsfluorescence polarization-based screening. homogenous assay system.fluorescence intensity-based screeningprof. michael famuloklaboratory of chemical biology university of bonn source of chemical librarieslcommercial sources (free of royalty)l-nci (http:/dtp.nci

12、./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) lopen collection 1 (90,000 compounds) lopen collection 2 (10,000 compounds)l-chemdiv (http

13、:/)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 chemical co. (1120 off-patient drugs)-microsources: the spectrum collection (2000)-sequoia

14、(a large collection)-nih brain bioactive compound collectionaptamer-guided heart-specific deliverymolecular medicine for heart diseasesengineering nanoparticlesdrug loadingtargetingcontrolled release (heat, magnetic field, ph), engineering the nanoparticle system such that the intracellular drug-release kine