A/Professor Jamie Vandenberg, MBBS PhDLaboratory Head, Molecular Cardiology and Biophysics DivisionA/Professor, University of New South Wales
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Mark Cowley Lidwill Research Program in Cardiac Electrophysiology
Division of Molecular Cardiology and Biophysics
Victor Chang Cardiac Research Institute
Level 6, Lowy Packer Building, 405 Liverpool Street
Darlinghurst, NSW 2010
Research Focus:
The coordinated spread of electrical impulses down the heart is required for it to pump blood efficiently. If this process becomes disordered the heart pumps inefficiently or may even stop, resulting in sudden death. The aim of the work in the Mark Cowley Lidwill Research Program in Cardiac Electrophysiology is to investigate situations where these electrical impulses become disordered and to understand the causes of such conditions.
Electrical impulses in the heart are controlled by ion-channels, molecular structures that facilitate the passage of ions into and out of cells. We have five major projects looking at different aspects of how ion channels work and how disturbances in ion channel function affects the heart:
1. Genotype-phenotype relationships in the congenital Long QT syndrome
2. Structure-function studies of HERG K+ channels
3. Molecular basis of drug binding to hERG K+ channels
4. Genotype-phenotype relationships in Familial Atrial Fibrillation
5. Structure-function studies of Two pore K+ channels
The Laboratory is equipped with state-of-the-art patch clamp electrophysiology and two electrode voltage clamp facilities, including voltage-clamp fluorimetry. We also have a fully equipped molecular biology laboratory, tissue culture facility and a Xenopus Aquarium. At present the group consists of 3 post-doctoral research fellows (Adam Hill, Stefan Mann, Tadeusz Marciniec ), one PhD student (Mark Perrin), two research associates (Ken Wyse, Mark Hunter) and one Honours sudent (David Wang). In additon we have established very productive collaborations with Professor Kuchel (mathematical modeling and NMR spectroscopy), Serdar Kuyucak (molecular dynamics simulations), Antony Varghese (Mathematical modeling), Antony Cooper (protein trafficking), Jon Skinner and Andrew Davies (Genotype-phenotype relationships in Long QT syndrome), Diane Fatkin and Raj Subbiah (Familai Atrial Fibrillation)
Genotype-phenotype relationships in congenital Long QT syndrome
The vast majority of cardiac arrhythmias occur in the context of pre-existing heart disease. However in some patients arrhythmias can occur in the absence of any structural abnormalities or damage to the heart. The commonest of these 1? arrhythmia syndromes is the congenital Long QT syndrome (LQTS). LQTS is a particularly devastating disorder as it typically results in sudden death in young people who are otherwise fit and healthy. Congenital LQTS is caused by mutations in the ion channel genes that regulate electrical activity in the heart. We are collaborating with Jon Skinner at the Cardiac Inherited Diseases Group in Auckland and Andrew Davies at the Royal Children?s Hospital and Genetic Health Services Victoria to investigate how clinically identified mutations in ion channel genes affect the electrical function of these channels.
Selected Publications
Structure Function studies of HERG K+ channels
There are multiple ion channels in the heart, each responsible for coordinating the passage of different impulses throughout the heart. The K+ ion channel encoded for by the human ether-a-go-go related gene (HERG) is of particular interest to the group. These ion channels have very unusual kinetics, which have been suggested to be important in the suppression of arrhythmias. Furthermore, malfunction of HERG K+ channels due to inherited mutations or inhibition by drugs can cause long QT syndrome a potentially fatal disorder. We are using a range of molecular biology, cell biology, electrophysiology, mathematical modeling, and structural biology techniques to investigate how HERG K+ channels work.
Selected publications
Molecular basis of drug binding to HERG K+ channels.
One of the most intriguing properties of hERG K+ channels is there remarkable promiscuity for binding a wide range of drugs. This is more than just an academic curiosity as drugs that inhibit hERG K+ channels can result in the so-called drug-induced long QT syndrome that lead to sudden cardiac death. This has become a major headache for the pharmaceutical industry and regulatory authorities around the world have now mandated that testing for binding to hERG K+ channels must be part of the pre-clinical assessment for all new drugs. We are using a range of molecular biology and mathematical modeling techniques to determine the molecular basis of drug binding to hERG with the ultimate aim of trying to develop better tests for rapidly assaying drug binding to the channels.
Familial Atrial Fibrillation
Atrial Fibrillation (AF) is the commonest clinically significant arrhythmia, affecting up to 10% of the population over 80 years of age. Classically AF is thought of as an acquired disease. However, in ~20% patients, AF occurs in the absence of any known risk factors and no known cardiac abnormalities ? these patients are often called lone fibrillators. These patients often have a family history of AF and we are testing the hypothesis that in some of these patients the disease is caused by an inherited mutation in a cardiac ion channel protein.
Selected Publications
Two-pore potassium channels
The family of two-pore potassium channels were only discovered quite recently. They are thought to be the molecular basis of "leak currents" in a wide range of cell types. However, these channels are not merely open pores that allow the slow leak of potassium ions. Rather, their activity is tightly regulated in response to a wide range of physiological and pathological stimuli. We are particularly interested in the regulation of the acid-sensitive members of the family, the TASK channels, which are widely expressed in the brain, kidneys and heart.
Selected publications
Post-doctoral Fellows
Adam Hill, PhD
Stefan Mann, PhD
PhD Students
Mark Perrin, MBBS, FRACP
Senior Research Assistants
Tadeusz Marciniec, PhD
Research Assistants
Mark Hunter, BSc
Ken Wyse, BSc
David Wang
Dr Diane Fatkin, VCCRI
Dr Daniela Stock, VCCRI
Dr Raj Subbiah, St Vincent's Hospital
Professor Philip Kuchel, University of Sydney
Dr Serdar Kuyucak, University of Sydney
Professor Glenn F. King, Institute for Molecular Bioscience
Professor Peter Hunter, University of Auckland
Dr Tony Varghese, University of Wisconsin
Vandenberg JI, Walker BD, Campbell TJ. HERG K+ channels: friend and foe. Trends Pharmacol Sci 2001; 22:240-6.
Vandenberg JI, Torres AM, Campbell TJ, Kuchel PW. The HERG K(+) channel: progress in understanding the molecular basis of its unusual gating kinetics. Eur Biophys J 2004; 33:89-97
Vandenberg JI, Varghese A, Lu Y, Bursill JA, Mahaut-Smith MP, Huang, C. L. Temperature dependence of human Ether-a-go-go Related Gene (hERG) K+ currents. Am J Physiol Cell Physiol 2006; 291:C165-75.
Clarke CE, Hill AP, Zhao J, Kondo M, Subbiah RN, Campbell TJ, Vandenberg JI. Effect of S5P {alpha}-helix charge mutants on inactivation of hERG K+ channels. J Physiol. 2006;573:291-304
Hill AP, Sunde M, Campbell TJ, Vandenberg JI. Mechanism of block of the hERG K+ channel by the scorpion toxin CnErg1. Biophys J. 2007;92:3915-29
Otway R, Vandenberg JL, Guo G, Varghese A, Castro ML, Liu J, Zhao JT, Bursil JA, Wyse KR, Crotty H, Baddeley O, Walker B, Kuchar D, Thorburn C, Fatkin D. Stretch-sensitive KCNQ1 mutation: a link between genetic and environmental factors in the pathogenesis of atrial fibrillation? J Am Coll Cardiol. 2007;49:578-586
Fatkin D, Otway R, Vandenberg JI. Genes and Atrial Fibrillation: a new look at an old problem. Circulation 2007;116:782-792.
Clarke CE, Veale EL, Wyse K, Vandenberg JI, Mathie A. The M1P1 loop of TASK3 K2P channels apposes the selectivity filter and influences channel function. J Biol Chem. 2008;283:16985-92
Perrin MJ, Kuchel PW, Campbell TJ, Vandenberg JI. Drug binding to the inactivated state is necessary but not sufficient for high-affinity binding to human ether-?-go-go-related gene channels. Mol Pharmacol. (In Press)
Ju P, Pages G, Riek RP, Chen PC, Torres AM, Bansal PS, Kuyucak S, Kuchel PW, Vandenberg JI. The pore domain outer helix contributes to both activation and inactivation of the hERG K+ channl. J Biol Chem (In press)
Zhao J et al. (2008) HERG G572S and G584S are two nearby pore domain mutations with very different phenotypes. (submitted)
Mark Cowley Lidwill (1878-1968),
Inventor of the Cardiac Pacemaker*
Mark Cowley Lidwill was born in Cheltenham in England on 7th April 1878 and emigrated with his parents to Melbourne, Australia, in 1894. He graduated with Honours in Medicine (MB 1902 BCh 1903) and in 1905 as MD (Melb). Later in 1911 the University of Sydney also awarded him an MD aeg (Syd).
Mark Cowley first made his mark as an anaesthetist. But his interests were broad. In 1913 Lidwill purchased his own electrocardiograph machine, the first in Sydney, which was the size of a piano and required the patient to sit with both hands and the left foot immersed in buckets of saline. Indeed it is in cardiology that he made his most memorable contribution, his use for the first time of cardiac pacing1. At the Australasian Medical Congress (BMA), Third Session 1929, held in Sydney, Lidwill presented a paper on Cardiac disease in relation to anaesthesia thus integrating his two medical interests. This article has become famous for the very first description of cardiac pacing, which was described in an Appendix to his main paper "The machine, as shown, requires only to be plugged into a lighting point and its use does not require very much intelligence. One pole is applied to a pad on the skin, say the left arm, and is saturated with strong salt solution. The other pole which consists of a needle insulated except at its point, is plunged into the ventricle and the machine is started. It may be necessary to alter the polarity of the poles and there is a switch for doing this. When the current is applied to the apparently dead body, the whole thorax and arm contract. I think if this machine were used, it would often save lives. There may be many failures, but one life in fifty or even a hundred, is a big advancement where there is no hope at all 2.
In his lifetime, Mark Lidwill shunned any honours. He was much more interested in spending time with students and passing on his knowledge to the next generation rather than attending official functions and meeting dignitaries. It is therefore particularly appropriate that the pioneering work of this great Australian be remembered in the form of a scholarship to a young cardiologist to promote understanding of the basic science of cardiac electrophysiology.
References
1. Baker B. Proceedings of the 2005 Sixth International Symposium on the History of Anaesthesia.
2. Lidwill MC. Cardiac disease and anaesthesia. Transactions Australasian Medical Congress 1929: 160-163 & Medical Journal Australia 1929; 2: 574 (Summary)
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