Contact Information

Anatomy, Physiology & Genetics (APG)


Uniformed Services University of the Health Sciences
4301 Jones Bridge Road
Bethesda, Maryland 20814
Phone: 301-295-3509
Office: C-2114 Lab: C-2111
Email: thomas.flagg@usuhs.edu

Thomas P. Flagg, Ph.D.

Assistant Professor, Anatomy, Physiology, and Genetics
Program Affiliation: Molecular and Cell Biology

Education History

B.S. Stevens Institute of Technology, Hoboken, NJ
Major: Chemical Biology; Minor: History
M.S. University of Maryland, Baltimore, MD
Major: Physiology
Ph.D. University of Maryland, Baltimore, MD
Major: Physiology
Postdoctoral
Department of Cell Biology and Physiology
Washington University School of Medicine, St. Louis, MO
Mentor: Colin G. Nichols, Ph.D.

Primary Research Interests

Overview
My laboratory is broadly interested in the role of cellular metabolism (or alterations in cellular metabolism) in regulating cardiac electrical and contractile function. Our major research focus is the sarcolemmal ATP-sensitive (KATP) potassium ion channel and its role in cardiac physiology. KATP channels are generally thought to act by sensing the levels of ATP and ADP inside the cell and adjusting membrane excitability, and consequently cell function, to match energy availability and usage. In so doing, these channels are essential in protecting the heart during metabolic stress such as occurs in myocardial ischemia. We employ a wide variety of experimental techniques to study KATP structure and function, ranging from the molecular to the whole animal level. These techniques include patch-clamp electrophysiology to directly measure channel function, standard molecular biology techniques to assess gene expression, cell biology techniques to define signaling pathways, genetic tools to modify channel function in vivo and measuring EKGs in the whole heart or animal. Currently, our projects fall into two major areas described below.

Molecular and genetic basis of chamber-specific KATP structure
KATP channels are formed by the coassembly of four inward rectifying potassium channel subunits (Kir6.1 or Kir6.2) with an ATP-binding cassette protein (SUR1 or SUR2). Any combination of subunits is possible and the molecular composition is a major factor determining how the channel responds to metabolic stress. We have recently discovered that the subunit composition of atrial and ventricular KATP channels is distinct. This appears to result from chamber-specific expression of the SUR1 and SUR2 subunits. We are now working to uncover the molecular mechanisms that control subunit expression in the heart. These studies include analysis of the SUR1 and SUR2 gene promoters to identify specific regulatory factors that control expression and examination of the role of epigenetic factors such as histone acetylation and DNA methylation in determining the chamber-specific structure of KATP. Ultimately, we hope to identify pathways that might be exploited to modulate KATP channel density in an effort to enhance the cardioprotective effects of KATP channels during ischemia and perhaps ameliorate the life-threatening arrhythmias that are associated with metabolic stress in the heart.

Functional consequences of KATP channel composition on atrial function
The subunit composition of the KATP channel determines the physiological and pharmacological properties of the channel that define the conditions when KATP channels might open. For example, it has been reported that the atrial KATP channel opens in response to cell stretch which is a major stimulus for atrial natriuretic peptide release, while ventricular KATP channels do not respond to stretch. Additionally, we observe that atrial KATP channels respond to more mild forms of metabolic inhibition than do ventricular channels, suggesting that atrial KATP channels may open more frequently than previously thought. The differential composition of the atrial KATP implies that it may serve a unique function in the atrium when compared to the ventricle. With this in mind, we are using a multifaceted approach to characterize the properties of atrial KATP channels and the outcome of channel opening on atrial function in health and disease. Using both native tissue isolated from wild type or transgenic mice with altered KATP channel activity as well as the HL-1 atrial myocyte model, we are probing the role of atrial KATP channels in regulating atrial natriuretic peptide release and working to define the molecular pathways that might underlie the release of this hormone that plays an important role in regulating systemic blood pressure and may also act to protect the heart. In addition, we are exploring anew the hypothesis that activation of atrial KATP channels is an important factor in the development or maintenance of atrial fibrillation, which affects roughly 2 million Americans and is a significant risk factor for the incidence of a stroke. Interestingly, many of the triggers of atrial fibrillation such as myocardial ischemia, heart failure, or sleep apnea are associated with metabolic changes in the myocardium that could trigger KATP activation, particularly since atrial KATP channels are more sensitive to metabolic inhibition as a result of their composition.

Collaborative Projects

Acetate and pyruvate effects on heart function
In addition to our principal interest in KATP channels, we have recently embarked on a collaborative project with Dr. Aryan Namboodiri and Dr. Rolf Bunger to explore the effect of acetate, pyruvate, and similar metabolites on cardiac function. Our preliminary evidence suggests that uptake and/or metabolism of these critical metabolic intermediates causes significant changes in myocardial contractility. We are currently investigating the molecular mechanisms underlying the changes in contractility and testing a possible link between acetate and pyruvate metabolism and intracellular Ca2+ cycling.

Selected Publications (complete list of publications)

1. Flagg, T.P., D. Enkvetchakul, J.C. Koster, and C.G. Nichols. Muscle KATP Channels: Recent Insights into Energy Sensing and Myoprotection. Physiol Re., 90: 799-829, 2010. [Abstract]
2. Flagg, T.P., H.T. Kurata, R. Masia, G. Caputa, M.A. Magnuson, D.J. Lefer, W.A. Coetzee, and C.G. Nichols. Differential Structure of Atrial and Ventricular KATP: Atrial KATP Channels Require SUR1. Circ Res, 103: 1458-1465, 2008. [Abstract]
3. Flagg, T.P., O. Cazorla, M.S. Remedi, T.E. Haim, M.A. Tones, A. Bahinski, R.E. Numann, A. Kovacs, J.E. Schaffer, C.G. Nichols, and J.M. Nerbonne. Ca2+-Independent Alterations in Diastolic Sarcomere Length and Relaxation Kinetics in a Mouse Model of Lipotoxic Diabetic Cardiomyopathy. Circ Res, 104: 95-103, 2009. [Abstract]
4. Glukhov, A.V., T.P. Flagg, V.V. Fedorov, I.R. Efimov, C.G. Nichols. 2010. Differential KATP channel pharmacology in intact mouse heart. J Mol Cell Cadiol. 48: 152-160, 2010. [Abstract]
5. Haim, T.E., W. Wang, T.P. Flagg, M.A. Tones, A. Bahinski, R.E. Numann, C.G. Nichols, J.M. Nerbonne. Palmitate attenuates myocardial contractility through augmentation of repolarizing Kv currents. J Mol Cell Cadiol, 48: 395-405, 2010. [Abstract]
6. Elrod, J.W., Harrell, M., Flagg, T.P., Gundewar, G., Magnuson, M.A., Nichols, C.G., Coetzee, W.A., and Lefer, D.J. The Role of SUR1 Subunits of KATP Channels in Myocardial Ischemia-Reperfusion Injury. Circulation, 117:1405-13, 2008. [Abstract]
7. Flagg, T.P., M.S. Remedi, R. Masia, J. Gomes, M. McLerie, A.N. Lopatin and C. G. Nichols. Transgenic Overexpression of SUR1 in the Heart Suppresses Sarcolemmal KATP. J Mol Cell Cardiol. 39:647-656, 2005 [Abstract]
8. Flagg, T.P., B. Patton, R. Masia, C. Mansfield, A.N. Lopatin, K.A. Yamada, and C.G. Nichols. Arrhythmia Susceptibility and Premature Death in Transgenic Mice Overexpressing Both SUR1 and Kir6.2[ N30,K185Q] in the Heart. Am J Physiol Heart Circ Physiol., 293: H836-H845, 2007. [Abstract]
9. Flagg, T.P., F. Charpentier, J. Manning-Fox, M.S. Remedi, D. Enkvetchakul, A. Lopatin, J.C. Koster, and C.G. Nichols. Remodeling Of Excitation-Contraction Coupling In Transgenic Mice Expressing ATP-Insensitive Sarcolemmal KATP. Am J Physiol Heart Circ Physiol 286: H1361-H1369, 2004. [Abstract]