心力衰竭的细胞分子生物学基础PKC激活和心力衰竭英文ppt课件.pptVIP

07/16/96 07/16/96 ## 07/16/96 ## 07/16/96 ## * 《规范》及指导原则适用于食品药品监管部门对第三类医疗器械批发/零售经营企业经营许可（含变更和延续）的现场核查，第二类医疗器械批发/零售经营企业经营备案后的现场核查，以及医疗器械经营企业的各类监督检查 *  Wei DUANSchool of MedicineDeakin UniversityMelbourne, Australia Molecular Medicine for Heart Failure Isozyme-specific Modulation of PKC? Heart Failure in Australia The prevalence of heart failure in Australia is ~6.3% . The 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, 4th ed Molecular Cell Biology underlying heart failure: PKC Activation and Heart Failure Circulation Research. 2007;101:195 J. Clin. Invest., 115:527,2005 Activation of PKC? and Heart Failure PKC? is activated by Gq/G11 -PLC? -IP3-SR-released Ca++ and DAG Sarcoplasmic Reticulum) wo Nature Medicine, 10:239,2004 Protein Phosphatase-1 Phospholamban P ca++ uptake, increased Ca++ release contractile force) Sarcoplasmic reticular calcium uptake protein PKCa Ca++ cycling Reduced 1-contraction strength 2—ralaxation 3—Cardiac reserve PKCa is activated by Ca++, stress agonists, pressure load, myocardial infarction, angiotensin, Transition in failing hearts from adequate compensation To advanced failure Protein Phosphatase Inhibitor-1 Calcium handling proteins: PLB, SERCA-2a Domain Structure of PKC Most available kinase inhibitors are ATP-binding site analogues Lack of specificity:Nat. Biotechnol. 23:329-336, 2005Biochem. J. 351:95-105, 2000. ATP N-Lobe C-Lobe Staurosporine (originally developed as a PKC inhibitor) Is there such a thing as a “Specific” kinase inhibitor? 3-D structure of PKA DIFFICULTIES in structural determination of C-tail Role of the very C-termini of PKCs N-Lobe C-Lobe Study of the function of C-terminus of PKC-alpha The last 10 amino acid residues are essential for the catalytic co