Faculty of Medicine Masaryk University

 

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Tibor Stračina
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Research group Cellular Electrophysiology

Actualities

In 2016, we offer 4 available PhD positions with the following topics:

  1. Analysis of changes of ionic channel properties caused by mutations associated with inherited arrhythmias
    supervisor: Assoc. Prof. MUDr. Markéta Bébarová, Ph.D. (mbebar@med.muni.cz)
    annotation:
    Inherited arrhythmias (e.g. long QT syndrome) are rare, life-threatening diseases caused by mutations in cardiac ionic channels. Study of the identified mutations considerably helps to understand arrhythmogenic mechanisms in concrete patients. The elucidated mechanisms may be, up to a certain extent, generalized for the mutations showing similar changes of ionic channel function. Moreover, the functional analysis enables to consider prognosis of the disorder which may be manifested by a fatal arrhythmia for the first time. The laboratory work will include cell line culture and its transient transfection with human ionic channels, both the wild type channels and channels encompassing selected mutation identified in a concrete patient from the database of the Department of Internal Cardiology Medicine, FH Brno. Subsequently, the student will measure basic electrophysiological characteristics of the transiently expressed ionic channels using the whole cell patch clamp technique. The goal of the study will be to find out functional differences between the wild type and mutant channels, best leading to a prospective explanation of the arrhythmogenesis and to an estimation of the risk resulting from the mutation carriage.
     
  2. Method estimating capacity of the t-tubular system in intact cells
    supervisor: Assoc. Prof. MUDr. Markéta Bébarová, Ph.D. (mbebar@med.muni.cz)
    supervisor-specialist: Assoc. Prof. RNDr. Jiří Šimurda, CSc.
    annotation:
    Two components of the cell membrane capacity of a cardiomyocyte may be distinguished – the capacity of surface membrane and the capacity of t-tubular membrane. Distribution of the transport molecules including ionic channels differs in these membrane components. The method called detubulation destroys the t-tubular membrane by applying osmotic shock. Hence, it is possible to estimate fraction of the t-tubular membrane capacity on the total membrane capacity when the membrane capacity is measured before and after detubulation. The detubulation is, however, irreversible, it does not allow study of dynamic changes of t-tubular structure. The goal of this thesis will be to develop newly suggested method of estimation of the t-tubular membrane capacity which will allow measurement of ratio of the t-tubular and surface membrane in intact cells. Thus, it may be applied repeatedly in the same cell, for example before and after application of selected substances. Both experimental measurement of the cell membrane capacity and ionic currents in isolated cardiomyocytes (using the whole cell patch clamp technique) and mathematical modelling (using Matlab) will be included. Hence, we prefer a technically skilled student, best from the field of Biomedical Engineering.
     
  3. Measurement and analysis of electrophysiological characteristics of the membrane transport system of cardiac cells under metabolic inhibition
    supervisor: Assoc. Prof. MUDr. Markéta Bébarová, Ph.D. (mbebar@med.muni.cz)
    supervisor-specialist: Assoc. Prof. Ing. Michal Pásek, Ph.D.
    annotation:
    Reduction of the blood flow in coronary vessels decreases delivery of oxygen and nutrients to the cardiac cells which results in inhibition of the cellular metabolism and, thus, in a decrease of the intracellular concentration of ATP and of pH. These changes essentially influence activity of the membrane ionic channels and other transporters, thus, also the electromechanical activity of the cells. The goal of the study will be to measure and analyse changes of electrophysiological characteristics of the membrane transport system (ionic currents) in isolated cardiac cells (whole cell patch clamp technique) at metabolic inhibition.
     
  4. Computational modelling of effect of ion concentration changes in extracellular spaces on electromechanical activity of cardiac cells under metabolic inhibition
    supervisor: Assoc. Prof. Ing. Michal Pásek, Ph.D. (mpasek@med.muni.cz)
    annotation:
    Our recently published mathematical models of cardiac ventricular myocytes showed that activity-induced membrane transport of ions causes significant changes of ion concentrations in extracellular spaces (t-tubules and extracellular clefts). In physiological conditions, these ion concentration changes reduce the cellular Ca2+ influx and thereby the intracellular Ca2+ transients that determine the strength of cellular contractions. However, the magnitude of ion concentration changes in extracellular spaces and their effect on cellular activity in pathological conditions has not been explored so far. Under metabolic inhibition (a condition leading to a reduction of intracellular ATP), these ion concentration changes and their feedback effect might by even higher because of activation of potassium ATP sensitive current (IKATP). The aim of this work is to assess the extent of ion concentration changes in extracellular spaces under metabolic inhibition and to explore their effect on electromechanical activity of cardiomyocytes by means of simulations on cellular mathematical models.

It is suitable to visit our laboratory in advance. In case of interest, please contact supervisor of the selected topic in time.

About the group

The research group of Cellular Electrophysiology originates from the fruitful history of electrophysiological experiments on the multicellular level which were performed at the Department of Physiology FM MU from 1960s. Within the last 10 years, our research activities are focused namely on analyses of effects of various drugs used in the clinical medicine (e.g. the antiarrhythmic drug ajmaline and the antipsychotic drug perphenazine) and also of addictive drugs (ethanol and nicotine) on ionic membrane currents and action potential configuration of both ventricular and atrial cardiac cells enzymatically isolated from hearts of small laboratory animals. In parallel, we also deal with mathematical simulations analysing the drug effects and also of other events, for example of the impact of t-tubules on the function of ventricular cardiomyocytes. Recently, we have newly introduced measurement of ionic currents through human ionic channels transiently expressed in a cell line. This method enables to deal with a completely new research area, for example to analyse the functional impact of ionic channel mutations associated with inherited arrhythmias (e.g. long QT syndrome, Brugada syndrome) or with other monogenic inherited diseases.

People

Coordinator Assoc. Prof. MUDr. Markéta Bébarová, Ph.D.
 
Researchers Assoc. Prof. Ing. Michal Pásek, Ph.D.
Assoc. Prof. MUDr. Milena Šimurdová, CSc.
Assoc. Prof. RNDr. Ing. Jiří Šimurda, CSc.
Peter Matejovič
 
Ph.D. students Mgr. Zuzana Hořáková (the study interrupted on January 1, 2016)
 
Undergraduate students Roman Kula (P-PooL)
Adam Vejmělek (P-PooL)
Bc. Lucie Šedová (diploma thesis)
Júlia Šatková (bachelor thesis)
 
Technicians Branislava Vyoralová
 

Areas of focus

  • analysis of changes of electrophysiological properties of cardiac cells (i.e. ionic currents and action potential configuration) induced by pharmacological agents
  • analysis of functional impact of t-tubules on cardiac cells
  • analysis of functional impact of ionic channel mutations associated with inherited arrhythmias (e.g. long QT syndrome, Brugada syndrome)

Established methods and experimental models

  • whole cell patch clamp measurement on ventricular (B) and atrial (C) cardiac cells freshly enzymatically isolated from hearts of small laboratory animals perfused according Langendorff (A)
  • whole cell patch clamp measurement on isolated cardiac cells following their short-term incubation
  • whole cell patch clamp measurement on a cell line transiently expressing human ionic channels (D)
  • mathematical modelling (E) – our original published models may be used: human, rat and guinea-pig ventricular cell model; human and rat atrial cell models are in preparation

Cellular Electrophysiology

Research grants

  • 2016: Kardiovaskulární systém: od modelu přes terapii k prevenci („Cardiovascular system: from model through therapy to prevention“; MUNI/A/1365/2015; investor: MU – specific research project; principal investigator: prof. M. Nováková)
  • 2015: Kardiovaskulární systém od buňky k lůžku pacienta („Cardiovascular system from cell to bedsight“; MUNI/A/1326/2014; investor: MU - specific research project; principal investigator: prof. M. Nováková)
  • 2013 – 2015: Effect of ethanol and its principle metabolite acetaldehyde on cardiac inward rectifier potassium currents: a link to atrial fibrillation related to alcohol consumption? (NT14301-3/2013; investor: IGA of the Ministry of Health of the CR; principal investigator: doc. M. Bébarová)
  • 2003: Effects of ajmaline on membrane currents in cardiomyocytes (FRVS/492/2003; investor: University Development Fund of the Ministry of Education, Youth and Sports of the CR; principal investigator: doc. M. Bébarová)
  • 2002 – 2004: Quantitative analysis of effect of tubular system on electrical activity of cardiac cells (GP204/02/D129; investor: Czech Science Foundation; principal investigator: doc. M. Pásek)

Co-operations

  • Dr. Georges Christé (Inserm, Lyon, France)
  • Prof. Clive H. Orchard (University of Bristol, Bristol, UK)
  • Prof. Paul G.A. Volders (Maastricht University, Maastricht, Netherlands)
  • RNDr. Jan Hošek, Ph.D. (University of Veterinary and Pharmaceuticals Sciences Brno)
  • Assoc. Prof. MUDr. Tomáš Novotný, Ph.D. (Department of Internal Cardiology Medicine, FH Brno)

Defended Ph.D. theses

  • 2005: Effect of antiarrhythmic drug ajmaline on electrophysiological properties of working cardiomyocyte (MUDr. Markéta Bébarová; supervisor: Assoc. Prof. RNDr. Ing. Jiří Šimurda, CSc.)
Selected publications
  • Pásek M, Bébarová M, Christé G, Šimurdová M, Šimurda J. Acute effects of ethanol on action potential and intracellular Ca2+ transient in cardiac ventricular cells: a simulation study. Med Biol Eng Comput 2015 Aug 18 (in press).
  • Bébarová M, Matejovič P, Šimurdová M, Šimurda J. Acetaldehyde at clinically relevant concentrations inhibits inward rectifier potassium current IK1 in rat ventricular myocytes. Physiol Res 2015;64:939-943.
  • Bébarová M, Matejovič P, Pásek M, Šimurdová M, Šimurda J. Dual effect of ethanol on inward rectifier potassium current IK1 in rat ventricular myocytes. J Physiol Pharmacol 2014;6:497-509.
  • Pásek M, Šimurda J, Orchard CH. Effect of Ca2+ efflux pathway distribution and exogenous Ca2+ buffers on intracellular Ca2+ dynamics in the rat ventricular myocyte: a simulation study. Biomed Res Int 2014;2014:920208.
  • Hrabcová D, Pásek M, Šimurda J, Christé G. Effect of ion concentration changes in the limited extracellular spaces on sarcolemmal ion transport and Ca2+ turnover in a model of human ventricular cardiomyocyte. Int J Mol Sci 2013;14:24271-24292.
  • Bébarová M. Arrhythmogenesis in Brugada syndrome: Impact and Constrains of Current Concepts. Int J Cardiol 2013;167:1760-1771.
  • Pásek M, Šimurda J, Orchard CH. Role of t-tubules in the control of trans-sarcolemmal ion flux and intracellular Ca2+ in a model of the rat cardiac ventricular myocyte. Eur Biophys J 2012;41:491-503.
  • Bébarová M. Advances in patch clamp technique: towards higher quality and quantity. Gen Physiol Biophys 2012;3):131-140.
  • Bébarová M, Matejovič P, Pásek M, Ohlídalová D, Jansová D, Šimurdová M, Šimurda J. Effect of ethanol on action potential and ionic membrane currents in rat ventricular myocytes. Acta Physiol (Oxf) 2010;200:301-314.
  • Kilianová A, Bébarová M, Beránková K, Pásek M, Bartošová L. Effect of newly synthesized compounds 44Bu a 444 on QRS-complex width and fast sodium current: differences between isomers. Acta Vet Brno 2010;79:41-49.
  • Bébarová M, Matejovič P, Pásek M, Jansová D, Šimurdová M, Nováková M, Šimurda J. Effect of antipsychotic drug perphenazine on fast sodium current and transient outward potassium current in rat ventricular myocytes. Naunyn-Schmiedebergs Arch Pharmacol 2009;380:125-133.
  • Pásek M, Šimurda J, Orchard CH, Christé G. A model of the guinea-pig ventricular cardiac myocyte incorporating a transverse-axial tubular system. Prog Biophys Mol Biol 2008;96:258-280.
  • Pásek M, Brette F, Nelson A, Pearce C, Qaiser A, Christe G, Orchard CH. Quantification of t-tubule area and protein distribution in rat cardiac ventricular myocytes. Prog Biophys Mol Biol 2008;96:244-257.
  • Pásek M, Šimurda J, Christé G, Orchard CH. Modelling the cardiac transverse-axial tubular system. Prog Biophys Mol Biol 2008;96:226-243.
  • Bébarová M, Matejovič P, Pásek M, Nováková M. Effect of haloperidol on transient outward potassium current in rat ventricular myocytes. Eur J Pharmacol 2006;550:15-23.
  • Pásek M, Šimurda J, Christé G. The functional role of cardiac T-tubules explored in a model of rat ventricular myocytes. Philos Trans A Math Phys Eng Sci 2006;364:1187-1206.
  • Bébarová M, Matejovič P, Pásek M, Šimurdová M, Šimurda J. Effect of ajmaline on action potential and ionic currents in rat ventricular myocytes. Gen Physiol Biophys 2005;24:311-325.
  • Bébarová M, Matejovič P, Pásek M, Šimurdová M, Šimurda J. Effect of ajmaline on transient outward current in rat ventricular myocytes. Gen Physiol Biophys 2005;24:27-45.
  • Pásek M, Šimurda J. Quantitative modelling of interaction of propafenone with sodium channels in cardiac cells. Med Biol Eng Comput 2004;42:151-157.
  • Pásek M, Christé G, Šimurda J. A quantitative model of the cardiac ventricular cell incorporating the transverse-axial tubular system. Gen Physiol Biophys 2003;22:355-368.
  • Šimurda J, Šimurdová M, Pásek M, Bravený P. Quantitative analysis of cardiac electrical restitution. Eur Biophys J 2001;30:500-514.
 

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