Robert S. Kass, PhD

Profile Headshot

Overview

The focus of Dr. Kass' research program is the structure and function of ion channels that are expressed primarily in the heart. Dr. Kass has directed NIH and/or NSF sponsored research for forty-two years that has contributed to our understanding of the fundamental cellular and molecular basis of cardiac electrical activity through a multidisciplinary approach bridging basic biophysical and clinical science. Contributions from this work include the cellular basis of calcium-dependent arrhythmogenic activity in the heart, basic mechanisms of action of calcium channel blocking drugs, and the molecular events underlying the control of the duration of electrical events in the heart during sympathetic nerve stimulation. His laboratory has focused on understanding the molecular physiology and pharmacology of congenital arrhythmias. These arrhythmias are caused by inherited mutations in genes coding for ion channels and/or ion channel related proteins expressed in the heart. This work has contributed to an understanding of gene-specific risk factors caused by mutation-induced changes in heart ion channel activity, and to the development of a mutation-specific approach to manage these disorders. The mutation-specific therapeutic strategy, verified in genotyped patients, has established the principle that two variants of the same genetic disorder require dramatically different therapeutic strategies for disease management based on biophysical properties of specific genetic lesions. This approach has evolved from close collaborations with clinical colleagues in which information is shared from clinic to basic laboratory and back to clinic. Additional studies are aimed at unraveling the structural basis of mutation-induced, and potentially lethal, disease phenotypes using approaches such as voltage-clamp fluorometry to directly measure movement of gating machinery in the ion channel of interest as well as biochemical methods of directly probing structures of region of ion channels that are hotspots for disease-causing mutations and the use of computer-based modeling to understand both structure and functional consequences of these mutations. Work has additionally more recently focused on potassium ion channel mutations that underlie a form of heritable pulmonary arterial hypertension.  This work has provided information not only of novel pathways that contribute to this disease, but also to new routes of therapeutic management of this disorder. The goal of this approach is to unmask new and specific targets for the development of anti-arrhythmic drugs. Currently, work in the laboratory focused on the study of mechanisms underlying heritable arrhythmias in the context of complex genetic backgrounds has studied the cellular electrophysiology of cardiomyocytes differentiated from inducible pluripotent stem cells derived from family members of patients harboring disease-causing mutations. This approach has offered opportunities to screen drugs for effective disease management when multiple genes may be involved in the disease phenotype.

Academic Appointments

  • Hosack Professor of Pharmacology
  • Alumni Professor of Pharmacology (in Neuroscience)

Gender

  • Male

Credentials & Experience

Education & Training

  • BSc, 1968 Physics, University of Illinois, Urbana
  • PhD, 1972 Physics, University of Michigan, Ann Arbor

Honors & Awards

Phi Beta Kappa

Research

The focus of Dr. Kass' research program is the structure and function of ion channels that are expressed primarily in the heart. Dr. Kass has directed NIH and/or NSF sponsored research for forty-two years that has contributed to our understanding of the fundamental cellular and molecular basis of cardiac electrical activity through a multidisciplinary approach bridging basic biophysical and clinical science.  Contributions from this work include the cellular basis of calcium-dependent arrhythmogenic activity in the heart, basic mechanisms of action of calcium channel blocking drugs, and the molecular events underlying the control of the duration of electrical events in the heart during sympathetic nerve stimulation.  His laboratory has focused on understanding the molecular physiology and pharmacology of congenital arrhythmias. These arrhythmias are caused by inherited mutations in genes coding for ion channels and/or ion channel related proteins expressed in the heart. This work has contributed to an understanding of gene-specific risk factors caused by mutation-induced changes in heart ion channel activity, and to the development of a mutation-specific approach to manage these disorders. The mutation-specific therapeutic strategy, verified in genotyped patients, has established the principle that two variants of the same genetic disorder require dramatically different therapeutic strategies for disease management based on biophysical properties of specific genetic lesions. This approach has evolved from close collaborations with clinical colleagues in which information is shared from clinic to basic laboratory and back to clinic. Additional studies are aimed at unraveling the structural basis of mutation-induced, and potentially lethal, disease phenotypes using approaches such as voltage-clamp fluorometry to directly measure movement of gating machinery in the ion channel of interest as well as biochemical methods of directly probing structures of region of ion channels that are hotspots for disease-causing mutations and the use of computer-based modeling to understand both structure and functional consequences of these mutations. Work has additionally more recently focused on potassium ion channel mutations that underlie a form of heritable pulmonary arterial hypertension.  This work has provided information not only of novel pathways that contribute to this disease, but also to new routes of therapeutic management of this disorder. The goal of this approach is to unmask new and specific targets for the development of anti-arrhythmic drugs. Currently, work in the laboratory focused on the study of mechanisms underlying heritable arrhythmias in the context of complex genetic backgrounds has studied the cellular electrophysiology of cardiomyocytes differentiated from inducible pluripotent stem cells derived from family members of patients harboring disease-causing mutations.  This approach has offered opportunities to screen drugs for effective disease management when multiple genes may be involved in the disease phenotype.

Research Interests

  • Biophysics/Ion Channels
  • Cellular/Molecular/Developmental Neuroscience

Grants

MODULATION OF KCNQ1 CHANNEL ACTIVITY (Federal Gov)

Apr 1 2019 - Dec 31 2022

CALCIUM-DEPENDENT SPONTANEOUS ACTIVITY AS A NOVEL THERAPEUTIC TARGET OF INHERITED ARRHYTHMIA STUDIED IN HUMAN INDUCED PLURIPOTENT STEM CELL DERIVED CARDIAC MYOCYTES (NY State Gov)

Jun 1 2014 - May 31 2020

CLINICAL & BASIC SCIENCE STUDIES IN LONG QT SYNDROME TYPE 3 (LQT3) (Federal Gov)

Aug 1 2014 - Jun 29 2019

INVESTIGATING MECHANISMS OF HUMAN KCNQ1 MODULATION BY SMALL-MOLECULE ACTIVATORS (Private)

Jan 1 2015 - Dec 31 2016

REGULATION OF ADENYLYL CYCLASE SIGNALING PATHWAYS (Federal Gov)

Sep 20 2013 - May 31 2015

MODULATION OF KCNQ1 CHANNEL ACTIVITY (Federal Gov)

May 1 2014 - Dec 31 2014

GILEAD SCIENCES INVESTIGATION OF GS-458967 IN HUMAN IPS CELL DERIVED CARDIOMYCTES (Private)

Mar 17 2011 - Jun 30 2014

MOLECULAR DETERMINANTS OF K+ CHANNEL REGULATION IN HEART (Federal Gov)

Feb 1 1993 - May 31 2014

MECHANISTIC STUDY OF AN INHERITED ARRHYTHMIA IN A COMPLEX GE NETIC BACKGROUND USING IPS CELL DERIVED CARDIOMYOCYTES. (NY State Gov)

Sep 1 2010 - Aug 31 2013

MECHANISTIC STUDY OF AN INHERITED ARRHYTHMIA IN A COMPLEX GENETIC BACKGROUND USING IPS CELL DERIVED CARDIOMYOCYTES. (NY State Gov)

Sep 1 2010 - Aug 31 2013

NANION SYNCRO PATCH 96 (Federal Gov)

Jul 20 2012 - Jul 19 2013

MODELING PATHOGENESIS AND TREATMENT OF LQT3 USING GENETICALLY ENGINEERED HUMAN EMBRYONIC STEM CELLS (Private)

Jun 1 2010 - Jun 30 2013

TRAINING PROGRAM IN PHARMACEUTICAL SCIENCES (Federal Gov)

Jul 1 2008 - Jun 30 2013

MOLECULAR PHARMACOLOGY OF AN INHERITED HEART DISEASE (Federal Gov)

Jul 5 2007 - May 31 2013

MOLECULAR BASIS OF SUDDEN CARDIAC DEATH (Federal Gov)

Apr 1 2001 - Mar 31 2013

CALCIUM REGULATION OF CARDIAC ION CHANNELS (Private)

Jan 1 2007 - Dec 31 2011

PHARMACOGENOMICS AND ANTIARRHYTHMIC THERAPY: AN IN SILICO IN VESTIGATION (Federal Gov)

Apr 1 2010 - Mar 31 2011

ROLE OF AKT SIGNALING IN LEARNING AND SYNAPTIC PLASTICITY (Federal Gov)

Mar 1 2006 - Feb 28 2011

MOLECULAR DETERMINANTS OF RANOLAZINE BLOCK OF SUSTAINED HEART NA+ (SODIUM) CHANNEL ACTIVITY (Private)

Sep 1 2003 - Dec 31 2007

Selected Publications

Li Y, Hof T, Baldwin TA, Chen L, Kass RS, and Dessauer CW. Regulation of IKs Potassium Current by Isoproterenol in Adult Cardiomyocytes Requires Type 9 Adenylyl Cyclase. Cells. 2019;8(9).

Shandell MA, Quejada JR, Yazawa M, Cornish VW, and Kass RS. Detection of Nav1.5 Conformational Change in Mammalian Cells Using the Noncanonical Amino Acid ANAP. Biophys J. 2019;117(7):1352-63.

Bohnen MS, Ma L, Zhu N, Qi H, McClenaghan C, Gonzaga-Jauregui C, et al. Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension. Circ Genom Precis Med. 2018;11(10):e002087.

Peng G, Barro-Soria R, Sampson KJ, Larsson HP, and Kass RS. Gating mechanisms underlying deactivation slowing by two KCNQ1 atrial fibrillation mutations. Sci Rep. 2017;7:45911.

Barro-Soria R, Ramentol R, Liin SI, Perez ME, Kass RS, and Larsson HP. KCNE1 and KCNE3 modulate KCNQ1 channels by affecting different gating transitions. Proc Natl Acad Sci U S A. 2017;114(35):E7367-E76.

Bohnen MS, Roman-Campos D, Terrenoire C, Jnani J, Sampson KJ, Chung WK, et al. The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery. J Am Heart Assoc. 2017;6(9).

Bohnen MS, Peng G, Robey SH, Terrenoire C, Iyer V, Sampson KJ, et al. Molecular Pathophysiology of Congenital Long QT Syndrome. Physiol Rev. 2017;97(1):89-134.

Eng G, Lee BW, Protas L, Gagliardi M, Brown K, Kass RS, et al. Autonomous beating rate adaptation in human stem cell-derived cardiomyocytes. Nat Commun. 2016;7:10312.

Lorberbaum T, Sampson KJ, Chang JB, Iyer V, Woosley RL, Kass RS, et al. Coupling Data Mining and Laboratory Experiments to Discover Drug Interactions Causing QT Prolongation. J Am Coll Cardiol. 2016;68(16):1756-64.

Lorberbaum T, Sampson KJ, Woosley RL, Kass RS, and Tatonetti NP. An Integrative Data Science Pipeline to Identify Novel Drug Interactions that Prolong the QT Interval. Drug Saf. 2016;39(5):433-41.

Iyer V, Roman-Campos D, Sampson KJ, Kang G, Fishman GI, and Kass RS. Purkinje Cells as Sources of Arrhythmias in Long QT Syndrome Type 3. Sci Rep. 2015;5:13287.

Iyer V, Sampson KJ, and Kass RS. Modeling tissue- and mutation- specific electrophysiological effects in the long QT syndrome: role of the Purkinje fiber. PLoS One. 2014;9(6):e97720.

Terrenoire C, Wang K, Tung KW, Chung WK, Pass RH, Lu JT, et al. Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics. J Gen Physiol. 2013;141(1):61-72.