心力衰竭的细胞分子生物学基础：PKC激活 和 与心力衰竭-英文课件.pptVIP

* *  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 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 competence of PKC-alpha Intrinsic activity, protamine sulfate as substrate. DAG- activation Histone H1 as substrate S.S. Yeong, et al., J. Biol. Chem. 281:30768, 2006 The critical role of the very C-terminus of PKC-a in the activation of MAPK S.S. Yeong, et al., J. Biol. Chem. 281:30768, 2006 The critical role of the very C-terminus of PKC-a in Augmenting Melatonin-stimulated Neurite Outgrowth in Neuronal Cells S.S. Yeong, et al., J. Biol. Chem. 281:30768, 2006 Targeting “intrinsically disordered segment” instead of “druggable pocket”. Proof-of-principle data S.S. Yeong, et al., J. Biol. Chem., 2006 Aptamers (from Latin aptus, means “fitting”) Synthetic RNA, D