Dr. Gea-Ny Tseng
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Contact Information
Department of Physiology and Biophysics Virginia Commonwealth University P.O. Box 980551 Richmond, Virginia 23298-0551 Tel: 804-827-0811 Fax: 804-828-7382 email: gtseng@vcu.edu |
Gea-Ny Tseng received her Ph.D. degree in Pharmacology from Columbia University in 1985. After completing postdoctoral training in the laboratory of Dr. Brian F. Hoffman in 1988, she became a faculty member in the Department of Pharmacology at Columbia University. Dr. Tseng joined VCU in 1999.
Research
Our research interests are focused on the cardiac voltage-gated potassium (Kv) channels. Kv channels play a critical role in maintaining electrical stability of the heart. Mutations in the genes encoding Kv channel subunits can lead congenital arrhythmias: loss-of-function mutations in Kv channels can cause long QT (LQT) syndrome, while gain-of-function mutations in these channels can cause short QT or familial atrial fibrillation. Compared with other classes of ion channels (Na+, Ca2+, Cl-), the expression of K+ channels is more dynamic and thus is more prone to remodeling by pathological conditions of the heart. For example, many K+ channels in the heart have a half-life of a few hours, compared with a few days for Na+ and Ca2+ channels. Their expression level can be markedly altered by hypoxia or pressure- or volume-overload. These changes often lead to disturbances in cardiac electrical activity that are associated with a high risk for ventricular arrhythmia and sudden cardiac death due to myocardial infarction, myocardial hypertrophy, or heart failure. Therefore, cardiac Kv channels are important targets for antiarrhythmic drugs. Kv channel inhibitors may be used to combat short QT or atrial fibrillation, and Kv channel activators may provide therapeutic actions in congenital or drug-induced long QT. Currently available Kv channel inhibitors and activators suffer from a lack of specificity or unfavorable state-dependence of drug binding/unbinding. Thus, more work is needed to improve currently available Kv channel modulators and search for new lead compounds.
Our research projects have two interrelated directions. The first focuses on the structure-function relationship of cardiac Kv channels and mechanisms of action of clinical or experimental Kv channel modulators. There are two goals in the current project. The first one is to build three-dimensional (3-D) models for the 'rapid' delayed rectifier channel (IKr, hERG) and the 'slow' delayed rectifier channel (IKs, KCNQ1/KCNE1 complex, some probably with additional KCNE2) by combining experimentally determined spatial constraints and computational analysis based on available K channel crystal structures. Another major goal of this proposal is to identify the binding sites and mechanisms of action of a group of novel IKr/hERG activators, some of which have shown great promise in combating drug-induced acquired long QT syndrome. We combine experience and expertise in mutagenesis and biophysical/biochemical characterization of channel function in the lab, and collaborations with leading experts in the areas of molecular modeling, drug docking and NMR spectroscopy. We are positioning our group for the direction of target-based in silico design of novel therapeutic agents targeting IKr, IKs and other Kv channels. This research project is highly relevant to public health because: (1) the data will provide insights into the mechanisms by which channel mutations cause malfunctions, and (2) the data will provide information on how to design pharmacological agents combating these channel malfunctions.
The second direction of our research projects is to study the mechanism of 'electrical remodeling' in aging or diseased hearts and how these remodeling phenomena can be modulated by dietary supplements. The current goal of this project is to study how fish oil supplements affect cardiac electrical activity. Many clinical trials have suggested that fish intake or fish oil supplement can protect post-myocardial infarction patients against sudden cardiac death (anti-arrhythmic effects). However, there is also indication suggesting that fish oil may have pro-arrhythmic effects (increasing the recurrence of VT/VF in some patients with implantable cardioverter/defibrillator, and increasing the mortality in angina patients). The latter cases provide a strong warning sign: fish oil may not be suitable for certain patients. More mechanistic studies into the biological activity of fish oil supplement are needed. In particular, information about the effects of chronic treatment with long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs, active ingredients in fish oil) on cardiac electrical activity is needed. Our project is designed to study the mechanisms for the anti-arrhythmic and possible pro-arrhythmic effects of fish oil supplement. We are testing the general hypothesis: chronic fish oil supplement produces anti-arrhythmic effects in infarcted hearts by modifying 'vulnerability factors' (vulnerability factors result from electrical and structural remodeling processes in infarcted hearts that promote arrhythmia), while acute effects of n-3 PUFAs can be pro-arrhythmic in diseased hearts when Na channel function and intercellular coupling are already compromised. This project is highly relevant to public health because although AHA recommends that general public and especially people at high risk for cardiovascular diseases take fish oil supplements, there have been no detailed molecular studies into how n-3 PUFAs affect cardiac function.
Teaching
I have been involved in the following courses/programs:
Cardiovascular Physiology (PHIS612) - Role as course director (2008 - )
Summer Undergraduate Program in Physiology & Biophysics - Role as Program Director (2008 - )
Cell Physiology (PHIS604) - Role as lecturer (2000 - )
Ion channel (PHIS620) - Role as session moderator (2000 - )
My lab has also hosted students for Undergraduate Research Internship, Master Thesis, and MD/PhD Lab Rotation.
Selected Publications
Tseng G-N. IKr: the hERG channel. J Mol Cell Cardiol. 2001;33:835-849.
Liu J, Zhang M, Jiang M, Tseng G-N. Structural and functional role of the extracellular S5-P linker in the HERG potassium channel. J Gen Physiol 2002;120:723-737
Tseng G-N, Sonawane KD, Korolkova YV, Zhang M, Liu J, Grishin E, Guy HR: Probing the outer mouth structure of hERG channel with peptide toxin foot printing and molecular modeling. Biophys J 2007;92:3524-3540
Zhang M, Jiang M, Tseng G-N. MinK-related peptide1 associates with Kv4.2 and modulates its gating function. A potential role as b subunit of cardiac transient outward channel. Circ Res 2001;88:1012-1019
Jiang M, Zhang M, Tang DG, Clemo HF, Liu J, Holwitt D, Kasirajan V, Pond AL, Wettwer E, and Tseng G-N: KCNE2 protein is expressed in ventricles of different species and changes in its expression contribute to electrical remodeling in diseased hearts. Circulation 2004;109:1783-17