Hund Lab for Excitable Cell Engineering
Research
Ca2+/calmodulin-dependent kinase II-dependent signaling in disease
Among the longest standing efforts of our group has been to understand the relationship between CaMKII dysregulation and cardiac disease. Specifically, we have developed and applied novel experimental and computational tools to determine the underlying molecular mechanism for CaMKII-dependent regulation of voltage-gated Na+ channel activity, cell membrane excitability, and heart function.
Representative publications
Glynn P, Musa H, Wu X, Unudurthi SD, Little S, Qian L, Wright PJ, Radwanski PB, Gyorke S, Mohler PJ, Hund TJ. Voltage-gated sodium channel phosphorylation at Ser571 regulates late current, arrhythmias, and cardiac function in vivo. Circulation. 2015; 132:567-577. PMCID: PMC4543581.
Koval OM, Snyder JS, Wolf RM, Pavlovicz RE, Glynn P, Curran J, Leymaster ND, Dun W, Wright PJ, Cardona N, Qian L, Mitchell CC, Boyden PA, Binkley PF, Li C, Anderson ME, Mohler PJ, and Hund TJ. Ca2+/calmodulin-dependent protein kinase II-based regulation of voltage-gated Na+ channel in cardiac disease. Circulation. 2012; 126:2084-2094. PMCID: PMC3811023.
Christensen MD, Dun W, Boyden PA, Anderson ME, Mohler PJ, and Hund TJ. Oxidized calmodulin kinase II regulates conduction following myocardial infarction: A computational analysis. PLoS Comput Biol. 2009; 5:e1000583. PMCID: PMC2778128.
Hund TJ, Decker KF, Kanter E, Mohler PJ, Boyden PA, Schuessler RB, Yamada KA, Y Rudy. Role of activated CaMKII in abnormal calcium homeostasis and INa remodeling after myocardial infarction: Insights from mathematical modeling. J Mol Cell Cardiol. 2008;45:420-8. PMCID: PMC2587155.
Spectrin-based pathways for regulation of cardiac excitability
Recent efforts from the Hund lab have focused on novel roles for the actin-associated protein βIV-spectrin in organizing ion channel macromolecular complexes in heart. While previous studies were restricted to brain, we have identified a critical role for βIV-spectrin in organizing specific ion channel regulatory complexes at the cardiomyocyte intercalated disc.
Representative publications
Hund TJ, Koval OM, Li J, Wright PJ, Qian L, Snyder JS, Gudmundsson H, Kline CF, Davidson NP, Cardona N, Rasband MN, Anderson ME, and Mohler PJ. A betaIV spectrin/CaMKII signaling complex is essential for membrane excitability in mice. J Clin Invest. 2010; 120:3508-19. PMCID: PMC2947241.
Hund TJ, Snyder JS, Wu X, Glynn P, Koval OM, Onal B, Leymaster ND, Unudurthi SD, Curran J, Camardo C, Wright PJ, Binkley PF, Anderson ME, Mohler PJ. βIV-spectrin regulates TREK-1 membrane targeting in heart. Cardiovasc Res. 2014; 102:166-75. PMCID:PMC3958619.
Smith SA, Sturm AC, Curran J, Kline CF, Little SC, Bonilla IM, Long VP, Makara M, Polina I, Hughes LD, Webb TR, Wei Z, Wright P, Voigt N, Bhakta D, Spoonamore KG, Zhang C, Weiss R, Binkley PF, Janssen PM, Kilic A, Higgins RS, Sun M, Ma J, Dobrev D, Zhang M, Carnes CA, Vatta M, Rasband MN, Hund TJ, Mohler PJ. Dysfunction in the βII spectrin-dependent cytoskeleton underlies human arrhythmia. Circulation. 2015; 131:695-708. PMCID:PMC4342332
Unudurthi SD, Wu X, Qian L, Amari F, Onal B, Li N, Makara MA, Smith SA, Snyder J, Fedorov VV, Coppola V, Anderson ME, Mohler PJ, Hund TJ. Two-pore K+ channel TREK-1 regulates sinoatrial node membrane excitability. J Am Heart Assoc. 2016; 5:e002865. PMCID:PMC4859279.
Cardiac pacemaking mechanisms
The sinoatrial node is collection of specialized cells in the right atrium, responsible for controlling the normal heart rhythm. Sinoatrial node dysfunction, characterized by clinical signs of bradycardia, sinus pause or arrest, and supraventricular arrhythmia, is common in elderly but may be observed at any age due to a host of factors. The Hund lab has utilized an integrative approach to identify cell and tissue level factors important for synchronization of spontaneous sinoatrial node activity.
Representative publications
Luo M, Guan X, Di L, Kutschke W, Gao Z, Yang J, Luczak ED, Glynn P, Swaminathan PD, Weiss RM, Yang B, Rokita AG, Sossalla S, Maier LS, Efimov I, Hund TJ, Anderson ME. Diabetes increases mortality after myocardial infarction by oxidizing CaMKII. J Clin Invest. 2013; 123:1262-74. PMCID: PMC3673230.
Swaminathan PD, Purohit A, Soni S, Voigt N, Singh MV, Glukhov AV, Gao Z, He JB, Luczak ED, Joiner MA, Kutschke W, Yang J, Donahue JK, Weiss RM, Grumbach IM, Ogawa M, Chen PS, Efimov I, Dobrev D, Mohler PJ, Hund TJ, and Anderson ME. Oxidized CaMKII causes sinus node dysfunction. J Clin Invest. 2011; 121:3277-88. PMCID: PMC3223923. co-corresponding author.
Wolf RM, Glynn P, Hashemi S, Zarei K, Mitchell CC, Anderson ME, Mohler PJ, and Hund TJ. Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: A computational analysis. Am J Physiol Heart Circ Physiol. 2013; 304:H1253-66. PMCID: PMC3652094. corresponding author.
Glynn P, Onal B, Hund TJ. Cycle length restitution in sinoatrial node cells: A theory for understanding spontaneous action potential dynamics. PLoS ONE. 2014; 9:e89049. PMCID:PMC3923067.
Unudurthi SD, Wu X, Qian L, Amari F, Onal B, Li N, Makara MA, Smith SA, Snyder J, Fedorov VV, Coppola V, Anderson ME, Mohler PJ, Hund TJ. Two-pore K+ channel TREK-1 regulates sinoatrial node membrane excitability. J Am Heart Assoc. 2016; 5:e002865. PMCID:PMC4859279.
Mathematical modeling of cardiac excitation and arrhythmias
The Hund lab has expertise in the development of detailed mathematical models of cardiac cells and tissue to study the role of cell signaling networks in congenital and acquired forms of cardiac arrhythmia. We have developed physiological models of the cardiac action potential that incorporate critical cell signaling and targeting pathways. Computer simulations have identified an important role for abnormal cell signaling in ion channel changes and cardiac arrhythmia following myocardial infarction, as well as in several congenital arrhythmia syndromes (e.g. Timothy syndrome, ankyrin-B syndrome). The overall goal of this research is to identify ionic mechanisms responsible for ion channel dysfunction and cardiac arrhythmia.
Representative publications
Onal B, Gratz D and Hund TJ. Ca2+/calmodulin-dependent regulation of atrial myocyte late Na+ current, Ca2+ cycling and excitability: a mathematical modeling study. Am J Physiol Heart Circ Physiol. 2017;313:H1227-H1239.
Glynn P, Onal B, Hund TJ. Cycle length restitution in sinoatrial node cells: A theory for understanding spontaneous action potential dynamics. PLoS ONE. 2014; 9:e89049. PMCID:PMC3923067.
Wolf RM, Glynn P, Hashemi S, Zarei K, Mitchell CC, Anderson ME, Mohler PJ, and Hund TJ. Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: A computational analysis. Am J Physiol Heart Circ Physiol. 2013; 304:H1253-66. PMCID: PMC3652094.
Wolf RM, Mitchell CC, Christensen MD, Mohler PJ, and Hund TJ. Defining new insight into atypical arrhythmia: a computational model of ankyrin-B-syndrome. Am J Physiol Heart Circ Physiol. 2010; 299:H1505-H1514.
Christensen MD, Dun W, Boyden PA, Anderson ME, Mohler PJ, and Hund TJ. Oxidized calmodulin kinase II regulates conduction following myocardial infarction: A computational analysis. PLoS Comput Biol. 2009; 5:e1000583. PMCID: PMC2778128.
Hund TJ, Decker KF, Kanter E, Mohler PJ, Boyden PA, Schuessler RB, Yamada KA, Y Rudy. Role of activated CaMKII in abnormal calcium homeostasis and INa remodeling after myocardial infarction: Insights from mathematical modeling. J Mol Cell Cardiol. 2008;45:420-8. PMCID: PMC2587155.
Hund TJ and Y Rudy. Rate dependence and regulation of the action potential and calcium transient in a canine cardiac ventricular cell model. Circulation. 2004; 110:3168-3174
