Establishment of reliable of human and canine atrial and ventricular action potential computer models  Page description

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Details of project

 
Identifier
109904
Type NN
Principal investigator Jost, Norbert László
Title in Hungarian Új megbízható humán és kutya pitvari és kamrai akciós potenciál potenciál számítógépes modellek kidolgozása
Title in English Establishment of reliable of human and canine atrial and ventricular action potential computer models
Keywords in Hungarian celluláris szívelektrofiziológia, in sillico model, akciós potenciál
Keywords in English cardiac cellular electrophysiology, in sillico modell, action potential
Discipline
Analysis, modelling and simulation of biological systems (Council of Medical and Biological Sciences)100 %
Panel Physiology, Pathophysiology, Pharmacology and Endocrinology
Department or equivalent Department of Pharmacology and Pharmacotherapy (University of Szeged)
Participants Corici, Claudia
Hartai, Teodóra
Horváth, András
Virág, László
Starting date 2013-10-01
Closing date 2017-09-30
Funding (in million HUF) 20.526
FTE (full time equivalent) 3.93
state running project





 

Final report

 
Results in Hungarian
A jelen projektnek célja volt, hogy az Oxfordi Egyetem Számítógépes Tudományok tanszékének a munkatársaival olyan komplex in sillico akciós potenciál modellek kifejlesztése, amelynek segítségével meg tudjuk állapítani, hogy az adott ionáram gátló szerek rendelkeznek vagy sem proaritmiás mellékhatásokkal. A projekt során 3 altémában végeztünk kísérletes munkát, amely során jelentős eredményeket értünk el. 1. Kifejlesztettünk olyan új in sillico akciós potenciál modelleket, amely segítségével meg tudjuk állapítani: i) hogy egy vegyület gátló hatása miként változtatja meg a proaritmiás hatásért felelős repolarizáció instabilitását („beat-to-beat” variabilitás); ii) milyen szerepet játszik a nátrium-kálium pumpa a szív aritmogenézisében. 2. Megvizsgáltuk a nátrium-kalcium cseremechanizmus (NCX) élet és kórtani szerepét. Új saját fejlesztésű és szabadalmaztatott NCX gátlók segítségével kimutattuk, hogy az NCX gátlása jelentős antiaritmiás hatással rendelkezik. 3. Megvizsgáltuk milyen szerepet játszanak egyes csatorna géndefektusok olyan ismert kardiális hatással rendelkező kórképekben, mint az Andersen-Tawill és a hosszú QT5 (LQT5) szindrómák. Kidolgoztunk és szabadalmaztattunk egy új transzgenikus LQT5 nyúlmodellt. A projekthez kapcsolódó kísérletes munkát 12 teljes tudományos dolgozatban publikáltuk (kumulatív impakt faktor 36.29). A projekt során 3 PhD doktori értekezés és védés történt a kooperációs munka eredményeképpen.
Results in English
The aim of the present project was to develop complex in silico action potential models, which may help to investigate the proarrhythmic potency of several ion channels blockers. The project was performed in an international cooperation with the researchers of the Department of Computer Sciences from Oxford University. The project consisted of 3 research subtopics. The following main results were obtained: 1. We have developed novel in silico action potential models, and by applying these models we have investigated that: i) how can an ion channel blocker modulate or modify the instability of the repolarization (beat-to-beat variability), which is known to be responsible for the proarrhythmic effect of the drugs; ii) what is the role of the sodium-potassium pump in the cardiac arrhythmogenesis. 2. We have investigated the physiological and pathophysiological role of the sodium- calcium exchanger (NCX). By applying some newly patented drugs developed by our group we demonstrated that the NCX-blocking effect has significant antiarrhythmic effect. 3. We have investigated the possible role of several ion channel gene mutations in some diseases having cardiac effects as the Andersen-Tawill and LongQT5 syndromes. The results obtained by implementing the present project have been published in 12 full lengths research papers having the cumulative impact factor of 36.29, and three PhD students defended their PhD degrees by presenting the research connected to this project.
Full text https://www.otka-palyazat.hu/download.php?type=zarobeszamolo&projektid=109904
Decision
Yes





 

List of publications

 
Muntean DM, Kiss L, Jost N, Baczkó I.: ATP-Sensitive Potassium Channel Modulators and Cardiac Arrhythmias: an Update, Curr Pharm Des. epub, 2014
Oliver J. Britton, Alfonso Bueno-Orovio, Laszlo Virag, Andras Varro, Blanca Rodriguez: Effect of Inter-Subject Variability in Determining Response to IKr Block in Human Ventricular Myocytes, Computing in Cardiology, 2014
N Jost, Zs Kohajda, A Horváth, N Morvai, J Levijoki, P Pollesello, T Koskelainen, L Otsomaa, I Leprán, J Gy Papp, A Varró, L Virág: Effects of ORM-10962, a novel inhibitor of sodium/calcium exchanger, on ion currents of canine cardiomyocytes, and its antiarrhythmic action in guinea pigs, Heart Rhythm, 11(5S), S172,, 2014
Petrus, Alexandra, Duicu O, Privistirescu A, Sturza A, Noveanu L, Muntean D, Baczkó I, Jost N: Modulation of mitochondrial respiration by novel ATP-sensitive poassium channel openers, Program and Abstract book of the European Section Meeting of the International Academy of Cardiovascular Sciences (IACS) (ISBN: 978-963-306-329-3), 2014
Muntean DM, Kiss L, Jost N, Baczkó I.: ATP-Sensitive Potassium Channel Modulators and Cardiac Arrhythmias: an Update, Curr Pharm Des. 21(8):1091-1102, 2015
Andersen-Tawil syndrome. Ördög B, Hategan L, Kovács M, Seprényi G, Kohajda Z, Nagy I, Hegedűs Z, Környei L, Jost N, Katona M, Szekeres M, Forster T, Papp JG, Varró A, Sepp R.: Identification and functional characterisation of a novel KCNJ2 mutation, Val302del, causing Andersen-Tawil syndrome., Can J Physiol Pharmacol, 93(7):569-75, 2015
Nagy N, Szél T, Jost N, Tóth A, Gy Papp J, Varró A.: Novel experimental results in human cardiac electrophysiology: measurement of the Purkinje fibre action potential from the undiseased human heart., Can J Physiol Pharmacol. 93(9):803-180, 2015
Baczkó I, Jost N, Varró A.: Cardioprotection and arrhythmias, Part I., 93(7):v. doi: 10.1139/cjpp-2015-0198, 2015
Baczkó I, Jost N, Varró A.: Cardioprotection and arrhythmias, Part 2, Can J Physiol Pharmacol, 93(9):v. doi: 10.1139/cjpp-2015-0400, 2015
Petruş A, Duicu OM, Sturza A, Noveanu L, Kiss L, Dănilă M, Baczkó I, Muntean DM, Jost N.: Modulation of mitochondrial respiratory function and ROS production by novel benzopyran analogues., Can J Physiol Pharmacol, 93(9):811-8, 2015
Nagy N, Kormos A, Kohajda Z, Szebeni Á, Szepesi J, Pollesello P, Levijoki J, Acsai K, Virág L, Nánási PP, Papp JG, Varró A, Tóth A: Selective Na(+) /Ca(2+) exchanger inhibition prevents Ca(2+) overload-induced triggered arrhythmias., Br J Pharmacol. 171(24):5665-5681, 2014
Orvos P, Virág L, Tálosi L, Hajdú Z, Csupor D, Jedlinszki N, Szél T, Varró A, Hohmann J.: Effects of Chelidonium majus extracts and major alkaloids on hERG potassium channels and on dog cardiac action potential - a safety approach., Fitoterapia, 100:156-165, 2015
Jost N, Muntean DM, Christ T.: Cardiac Arrhythmias: Introduction, Electrophysiology of the Heart, Action Potential and Membrane Currents, Pathophysiology and Pharmacotherapy of Cardiovascular Disease. Eds. Jagadeesh G, Balakumar P, Maungh-U K, pp 977-1002, Adis_Springer Publishing, doi: 10.1007/978-3-319-15, 2015
Christ T, Pecha S, Jost N.: Treatment of Atrial Fibrillation and Atrial Flutter., Pathophysiology and Pharmacotherapy of Cardiovascular Disease. Eds. Jagadeesh, Balakumar, Maungh-U, pp 977-1002, Adis_Springer Publish, doi: 10.1007/978-3-319-15961-4_50, 2015
Petruş A, Duicu OM, Sturza A, Noveanu L, Kiss L, Dănilă M, Baczkó I, Muntean DM, Jost N.: Modulation of mitochondrial respiratory function and ROS production by novel benzopyran analogues., Can J Physiol Pharmacol, 93(9):811-8, 2015
Jost N, Muntean DM, Christ T.: Cardiac Arrhythmias: Introduction, Electrophysiology of the Heart, Action Potential and Membrane Currents, Pathophysiology and Pharmacotherapy of Cardiovascular Disease. Eds. Jagadeesh G, Balakumar P, Maungh-U K, pp 977-1002, Adis_Springer Publishing, doi: 10.1007/978-3-319-15, 2015
Pueyo E, Dangerfield CE, Britton OJ, Virág L, Kistamás K, Szentandrássy N, Jost N, Varró A, Nánási PP, Burrage K, Rodríguez B: Experimentally-Based Computational investigation into beat-to-beat variability in ventricular repolarization and its response to ionic current inhibition, PLoS ONE 11(3): e0151461. doi:10.1371/journal.pone.0151461, 2016
Major P, Baczkó I, Hiripi L, Odening KE, Juhász V, Kohajda Z, Horváth A, Seprényi G, Kovács M, Virág L, Jost N, Prorok J, Ördög B, Doleschall Z, Nattel S, Varró A, Bősze Z: A novel transgenic rabbit model with reduced repolarization reserve: long QT syndrome caused by a dominant-negative mutation of KCNE1 gene, British Journal of Pharmacology, 173, 2046–2061, 2016
Baczkó I, Jost N, Virág L, Bősze Zs, Varró A: Rabbit models as tools for preclinical cardiac electrophysiological safety testing: importance of repolarization reserve, Progress in Biophys and Mol Biol, 121(2):157-168, 2016
Christ T, Kovács PP, Acsai K, Knaut M, Eschenhagen T, Jost N, Varró A, Wettwer E, Ravens U: Block of Na+/Ca2+ exchanger by SEA0400 in human right atrial preparations from patients in sinus rhythm and in atrial fibrillation, Eur J Pharmacol, 788, 286–293, 2016
Geramipour A, Kohajda Zs, Corici C, Prorok J, Szakonyi Zs, Oravecz K, Márton Z, Nagy N, Tóth A, Acsai K, Virág L, Varró A, Jost N: The investigation of the cellular electrophysiological and antiarrhythmic effects of a novel selective sodium-calcium exchanger inhibitor GYKB-6635 in canine and guinea p, Canadian Journal Physiology and Pharmacology, 94(10), 1090-1101, 2016
Pueyo E, Dangerfield CE, Britton OJ, Virág L, Kistamás K, Szentandrássy N, Jost N, Varró A, Nánási PP, Burrage K, Rodríguez B: Experimentally-Based Computational investigation into beat-to-beat variability in ventricular repolarization and its response to ionic current inhibition, PLoS ONE 11(3): e0151461. doi:10.1371/journal.pone.0151461, 2016
Major P, Baczkó I, Hiripi L, Odening KE, Juhász V, Kohajda Z, Horváth A, Seprényi G, Kovács M, Virág L, Jost N, Prorok J, Ördög B, Doleschall Z, Nattel S, Varró A, Bősze Z: A novel transgenic rabbit model with reduced repolarization reserve: long QT syndrome caused by a dominant-negative mutation of KCNE1 gene, British Journal of Pharmacology, 173, 2046–2061, 2016
Baczkó I, Jost N, Virág L, Bősze Zs, Varró A: Rabbit models as tools for preclinical cardiac electrophysiological safety testing: importance of repolarization reserve, Progress in Biophys and Mol Biol, 121(2):157-168, 2016
Geramipour A, Kohajda Zs, Corici C, Prorok J, Szakonyi Zs, Oravecz K, Márton Z, Nagy N, Tóth A, Acsai K, Virág L, Varró A, Jost N: The investigation of the cellular electrophysiological and antiarrhythmic effects of a novel selective sodium-calcium exchanger inhibitor GYKB-6635 in canine and guinea p, Canadian Journal Physiology and Pharmacology, 94(10), 1090-1101, 2016
Kohajda Z, Farkas-Morvay N, Jost N, Nagy N, Geramipour A, Horváth A, Varga RS, Hornyik T, Corici C, Acsai K, Horváth B, Prorok J, Ördög B, Déri S, Tóth D, Levijoki J, Pollesello P, Koskelainen T, Otsomaa L, Tóth A, Baczkó I, Leprán I, Nánási PP, Papp JG, Varró A, Virág L: The Effect of a Novel Highly Selective Inhibitor of the Sodium/Calcium Exchanger (NCX) on Cardiac Arrhythmias in In Vitro and In Vivo Experiments., PLoS One. 11(11):e0166041. doi: 10.1371/journal.pone.016604, 2016
Gurabi Z, Patocskai B, Györe B, Virág L, Mátyus P, Papp JG, Varró A, Koncz I: Different electrophysiological effects of the levo- and dextro-rotatory isomers of mexiletine in isolated rabbit cardiac muscle, Can J Physiol Pharmacol, 95(7):830-836. doi: 10.1139/cjpp-2016-0599, 2017
Britton OJ, Bueno-Orovio A, Virág L, Varró A, Rodriguez B: The Electrogenic Na+/K+ Pump Is a Key Determinant of Repolarization Abnormality Susceptibility in Human Ventricular Cardiomyocytes: A Population-Based Simulation Study, Front Physiol. 2017 May 5;8:278. doi: 10.3389/fphys.2017.00278. eCollection, 2017





 

Events of the project

 
2015-07-03 11:20:59
Résztvevők változása




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