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Task Force Ion Channel Cardiomyopathies

Functional Characterization of Ion channel Mutations

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Research

Aims

 

The understanding of the pathophysiological mechanisms of arrhythmogenesis in ion channel cardiomyopathies still remains a key scientific challenge. Over the last years, substantial progress has been made in the dissection of the molecular structure-function relationship of cardiac ion channel mutations. Functional relevance of these changes has been further issued in animal models. However, whereas these experiments allow deep insights into disease mechanisms on a molecular and cellular level, the influence on arrhythmogenesis in humans can only be hardly predicted.
Using an integrative approach of clinical phenotyping and genotyping in combination with molecular structure-function analyses, in vivo characterization, and bioinformatics, we established a multilevel translational approach to analyze the pathogenetic link between genotype and clinical phenotype.

For this purpose, close collaboration with scientific partners on campus (Zebrafish Unit, Interdisciplinary Center for Scientific Computing) as well as remote partners (KIT, Karlsruhe) has been established.
This combination of molecular electrophysiology with mathematical modeling allows exceptional insights into the mechanisms of electrophysiological processes. Furthermore this approach provides a unique possibility to assess antiarrhythmic properties of novel therapies.

 

Electrophysiological mechanisms of atrial fibrillation

Atrial fibrillation is the most frequent form of cardiac arrhythmias and is associated with increased mortality and an increased risk for stroke. The exact underlying electrophysiological mechanisms of atrial fibrillation are only poorly understood. Genetic defects, resulting in hereditary forms of atrial fibrillation are being increasingly identified. The characterization of the functional relation between these genetic defects and the development of atrial fibrillation can provide interesting insights into basic mechanisms of atrial fibrillation. 

 

 

Cooperation partners:

Dr.-Ing. -Gunnar Seemann (Institute of Biomedical Engineering, KIT Karlsruhe)

Prof. Olaf Dössel (Institute of Biomedical Engineering, KIT Karlsruhe)

Prof. Dobromir Dobrev (University of Heidelberg)

Dr. David Hassel (3rd Dept. of Internal Medicine, University Hospital Heidelberg)

 

 

Functional characterization of ion channel mutations

Within the framework of another DFG funded project the working group investigates the mechanisms of the development of arrhythmias in hereditary arrhythmia syndromes, like Brugada Syndrome, as well as Long- and Short-QT Syndromes. Goal of this integrative approach is it to establish the pathophysiological link between Genotype and Phenotype which allows predicting the proarrhythmic potential inherent in specific ion channel mutations. 

 

 


Cooperation partners:

Dr.-Ing. Gunnar Seemann (Institute of Biomedical Engineering, KIT Karlsruhe)

Prof. Olaf Dössel (Institute of Biomedical Engineering, KIT Karlsruhe)

PD Dr. med. Sebastian Ley (Dept. of Radiology, University Hospital Heidelberg)

Dr. med. Christian Veltmann (Med. Fakultät Mannheim, Uniklinik Heidelberg)

PD Dr. med. Rainer Schimpf (Med. Fakultät Mannheim, Uniklinik Heidelberg)

 

Simulation of excitation propagation within the cardiac conduction system

Within a cooperative project with the center for scientific calculating the working group develops novel mathematical models describing the excitation propagation in the cardiac conduction system. The goal is to get a better understanding of the involved processes.

 

 

Cooperation partner:

Dr. Sebastian Sager (Interdisciplinary Center for Scientific Computing, University of Heidelberg)

 

Scientific methods

The mutagenesis and expression of ion channel mutations is carried out with the help of molecular biological standard procedures. Expression analysis takes place with the help of western blots or fluorescence optical measurements. The structure-function-analyses of ion channel complexes are performed with patch-clamp-techniques in cell culture. In well-established cooperations the further characterization in animal models (zebra fish) and also computer models (3D-simulations) can be performed.

 

Cooperation partners:

Juniorprofessor Dr. rer. David Hassel (Innere Medizin III, Universitätsklinikum Heidelberg)

Dr.-Ing Gunnar Seemann (Institute of Biomedical Engineering, KIT Karlsruhe)

 

Staff

Prof. Dr. med. Eberhard P. Scholz

Group leader
Eberhard.Scholz[at]med.uni-heidelberg[dot]de
Tel: +49.6221.56.8570 oder 56.8476
Fax: +49.6221.56.8572
www.scholzlab.com

Dipl. Biol. Fathima Fischer
Deputy group leader
PhD Student (HBIGS Heidelberg)
Fathima.Fischer[at]med.uni-heidelberg[dot]de
Tel: +49.6221.56.8570 oder 56.8476
Fax: +49.6221.56.8572

 

Christine Jeckel
Lab technician


Julian Maier
Doctoral candidate


Stephan Vossel
Doctoral candidate


Nora Niemer
Doctoral candidate


Franziska Konrad
Doctoral candidate


Florian Welke
Doctoral candidate


Christoph Wolff
Doctoral candidate

Selected Publications

  1. Scholz EP, Welke F, Seyler C, Völker M, Bloehs R, Thomas D, Kathöfer S, Katus HA, Karle C, Zitron E. Central role of PKCalpha in isoenzyme-selective regulation of cardiac transient outward current Ito and Kv4.3 channels. J Mol Cell Cardiol 2011, 51(5):722-9.
  2. Meder B, Scholz EP (gleichberechtigter Erstautor), Hassel D, Wolff C, Just S, Berger IM, Patzel E, Karle C, Katus HA, Rottbauer W.: Reconstitution of Defective Protein Trafficking Rescues Long-QT Syndrome in Zebrafish. Biochem Biophys Res Comm 2011, 408(2):218-24.
  3. Scholz EP, Zitron E, Katus HA, Karle C: Cardiovascular ion channels as molecular targets of flavonoids. Cardiovascular Therapeutics 2010, 28(4):e46-52.
  4. Scholz EP, Niemer N, Hassel D, Zitron E, Bürgers HF, Bloehs R, Seyler C, Scherer D, Thomas D, Kathöfer S, Katus HA, Rottbauer WA, Karle CA.: Biophysical properties of zebrafish ether-à-go-go related gene potassium channels. Biochem Biophys Res Comm 2009, 381(2):159-64.
  5. Scherer D, Hassel D, Bloehs R, Zitron E, von Löwenstern K, Seyler C, Thomas D, Konrad F, Bürgers HF, Seemann G, Rottbauer W, Katus HA, Karle CA, Scholz EP. Selective noradrenaline reuptake inhibitor atomoxetine directly blocks hERG currents. Br J Pharmacol. 2009, 156(2):226-36.
  6. Hassel D*, Scholz EP* (*gleichberechtigter Erstautor), Trano N, Friedrich O, Just S, Meder B, Weiss DL, Zitron E, Marquart S, Vogel B, Karle CA, Seemann G, Fishman MC, Katus HA, Rottbauer W: Deficient Zebrafish Ether-a-Go-Go-Related Gene Channel Gating Causes Short-QT Syndrome in Zebrafish Reggae Mutants. Circulation 2008, 19;117(7):866-75.
  7. Seemann G, Carillo P, Weiss DL, Krueger MW, Dössel O, Scholz EP: Investigating Arrhythmogenic Effects of the hERG Mutation N588K in Virtual Human Atria. Lecture Notes in Computer Science 2008, 5528:144-153.
  8. Scholz EP, Konrad FM, Weiss DL, Zitron E, Kiesecker C, Bloehs R, Kulzer M, Thomas D, Kathöfer S, Bauer A, Maurer MH, Seemann G, Katus HA, Karle CA: Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656. Naunyn Schmiedebergs Arch Pharmacol 2007, 376:275-284.
  9. Scholz EP, Zitron E, Kiesecker C, Thomas D, Kathöfer S, Kreuzer J, Bauer A, Katus HA, Remppis A, Karle CA, Greten J: Orange flavonoid hesperetin modulates cardiac hERG potassium channel via binding to amino acid F656. Nutr Metab Cardiovasc Dis 2007, 17:666-675.
  10. Scholz EP, Alter M, Zitron E, Kiesecker C, Kathöfer S, Thomas D, Kreye VAW, Kreuzer J, Becker R, Katus HA, Greten J, Karle CA: In vitro modulation of HERG channels by organochlorine solvent trichlormethane as potential explanation for proarrhythmic effects of chloroform. Toxicol Lett 2006, 165:156-166.
  11. Zitron E*, Scholz E* (*gleichberechtigter Erstautor), Owen RW, Lück S, Kiesecker C, Thomas D, Kathöfer S, Niroomand F, Kiehn J, Kreye VAW, Katus HA, Schoels W, Karle CA: QTc prolongation by grapefruit juice and its potential pharmacological basis: HERG channel blockade by flavonoids. Circulation 2005, 111:835-838.
  12. Scholz EP, Zitron E, Kiesecker C, Lück S, Thomas D, Kathöfer S, Kreye VAW, Katus HA, Kiehn J, Schoels W, Karle CA: Inhibition of cardiac HERG channels by grapefruit flavonoid naringenin: implications for the influence of dietary compounds on cardiac repolarisation. Naunyn Schmiedebergs Arch Pharmacol 2005, 371:516-525.
  13. Scholz EP, Zitron E, Kiesecker C, Lueck S, Kathöfer S, Thomas D, Weretka S, Peth S, Kreye VAW, Schoels W, Katus HA, Kiehn J, Karle CA: Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired Long QT syndrome by antiparkinsonian drug budipine. Naunyn Schmiedebergs Arch Pharmacol 2003, 368:404-414.

Reserach Funding

Two projects are currently funded by grants from the German Research Foundationeutsche Forschungsgemeinschaft (DFG)

 

 

Fathima Fischer is supported as a PhD-Student at the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS).

 

 

 

Former Funding and Awards

  • Young-Investigator-Award (Medical Faculty of the University of Heidelberg)
  • Friedrich-Fischer-Award (University of Heidelberg)
  • Karl und Veronica Carstens-Scholarship
  • Rudolph-Fritz-Weiß-Award (German Society of Phytotherapy)

Vacancies

At present there are no job vacancies.

 

Contact details

Dr. med. Eberhard P. Scholz

 

Universitätsklinikum Heidelberg

Innere Medizin III (Kardiologie, Angiologie, Pneumologie)

Im Neuenheimer Feld 410

69120 Heidelberg

 

Tel.: +49.6221.56.8570 oder 56.8476

Fax.: +49.6221.56.33497

Email: Eberhard.Scholz[at]med.uni-heidelberg[dot]de

www.scholzlab.com

 

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