心力衰竭的細(xì)胞分子生物學(xué)基礎(chǔ)：PKC激活和心力衰竭-英文ppt課件

1、Molecular Medicine for Heart FailureIsozyme-specific Modulation of PKC lThe prevalence of heart failure in Australia is 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: Cec

2、il 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 FailureCirculation Research. 2019;101:195 J. Clin. Invest., 115:527,2005Activation of PKC and H

3、eart FailurePKC is activated by Gq/G11 -PLC -IP3-SR-released Ca+ and DAGSarcoplasmic Reticulum)Protein Phosphatase-1Phospholamban P ca+ uptake, increased Ca+ release & contractile force)Sarcoplasmic reticular calcium uptake proteinPKCa Ca+ cyclingReduced1-contraction strength2ralaxation3Cardiac

4、reservePKCa is activated by Ca+, stress agonists, pressure load, myocardial infarction, angiotensin, Transition in failing hearts fromadequate compensation To advanced failureProtein Phosphatase Inhibitor-1Calcium handling proteins:PLB, SERCA-2aDomain Structure of PKCATPN-LobeC-Lobe3-D structure of

5、PKADIFFICULTIES in structural determination of C-tailRole of the very C-termini of PKCsN-LobeC-LobeIntrinsic activity, protamine sulfate as substrate.DAG- activation Histone H1 as substrateS.S. Yeong, et al., J. Biol. Chem. 281:30768, 2019S.S. Yeong, et al., J. Biol. Chem. 281:30768, 2019The critica

6、l role of the very C-terminus of PKC-a in Augmenting Melatonin-stimulated Neurite Outgrowth in Neuronal CellsS.S. Yeong, et al., J. Biol. Chem. 281:30768, 2019S.S. Yeong, et al., J. Biol. Chem., 2019thrombintRNAC-terminus of PKC is exposed (accessible) from IP experimentsFluorescence Polarization-ba

7、sed screening. Homogenous assay system.Fluorescence Intensity-based screeningProf. Michael FamulokLaboratory of Chemical Biology University of Bonn lCommercial sources (free of royalty)l-NCI (/docs/misc/available_samples/dtp_indsamples.html)lStructural Diversity Set, version 1 (1,991

8、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 (chemdiv)l-ChemBridge Corporation (chembridge/chembridge/)lPartnership with pharmaslPartnership with acade

9、mial MOLECULAR LIBRARIES SCREENING CENTERS NETWORK (Established in 2019)l 9 Centers Sources of Current or Off-patient medications-Prestwick Chemical Co. (1120 off-patient drugs)-Microsources: The Spectrum Collection (2000)-Sequoia (a large collection)-NIH Brain Bioactive Compound collectionEngineering nanoparticlesDrug loadingTargetingControlled Release (heat, magnetic field, pH), engineering the nanoparticle system such that the intracellular drug-release kinetics is greater than the drug-efflux kinetics Drugs administered at