Robert S. Kass, PhD

Robert S. Kass, PhD

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Overview

Academic Appointments

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

Administrative Titles

  • Chairman, Department of Pharmacology

Gender

  • Male

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 thirty 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.  More recently 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. The goal of this approach is to unmask new and specific targets for the development of anti-arrhythmic drugs. Currently, work also is underway in the laboratory to study the mechanisms underlying heritable arrhythmias in the context of complex genetic backgrounds by investigating the cellular electrophysiology of cardiomyocytes differentiated from inducible pluripotent stem cells derived from family members of patients harboring disease-causing mutations.  This approach offers, for the first time, 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

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

Aug 1 2014 - Jun 29 2019

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 2017

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

Bankston, J.B., Sampson, K.J., Kateriya, S., I.W. Glaaser, D.L. Malito, W. Chung, and R.S. Kass. (2007).  A novel LQT-3 mutation disrupts an inactivation gate complex with distinct rate-dependent phenotypic consequences.  Channels 1:4, 273-280.

Chen L, Marquardt ML, Tester DJ, Sampson KJ, Ackerman MJ, Kass RS.(2007) Mutation of an A-kinase-anchoring protein causes long-QT syndrome. Proc Natl Acad Sci U S A. Dec 26;104(52):20990-5. Epub 2007 Dec 19.

Bankston JR, Yue M, Chung W, Spyres M, Pass RH, Silver E, Sampson KJ, Kass RS.,  (2007) A Novel and Lethal De Novo LQT-3 Mutation in a Newborn with Distinct Molecular Pharmacology and Therapeutic Response. PLoS ONE. Dec 5;2(12):e1258.

Sampson KJ, Terrenoire C, Cervantes DO, Kaba RA, Peters NS & Kass RS. (2008). Adrenergic regulation of a key cardiac potassium channel can contribute to atrial fibrillation: evidence from an IKs transgenic mouse. J Physiol 586, 627-637

Chung DY, Chan PJ, Bankston JR, Yang L, Liu G, Marx SO, Karlin A & Kass RS. (2009). Location of KCNE1 relative to KCNQ1 in the I(KS) potassium channel by disulfide cross-linking of substituted cysteines. Proc Natl Acad Sci U S A 106, 743-748.

Kurokawa J, Bankston JR, Kaihara A, Chen L, Furukawa T & Kass RS. (2009). KCNE variants reveal a critical role of the beta subunit carboxyl terminus in PKA-dependent regulation of the IKs potassium channel. Channels (Austin) 3, 16-24.

Lindegger N, Hagen BM, Marks AR, Lederer WJ & Kass RS. (2009). Diastolic transient inward current in long QT syndrome type 3 is caused by Ca2+ overload and inhibited by ranolazine. J Mol Cell Cardiol 47, 326-334.

Terrenoire C, Houslay MD, Baillie GS & Kass RS. (2009). The cardiac IKs potassium channel macromolecular complex includes the phosphodiesterase PDE4D3. J Biol Chem 284, 9140-9146.

Bankston JR & Kass RS. (2010). Molecular determinants of local anesthetic action of beta-blocking drugs: Implications for therapeutic management of long QT syndrome variant 3. J Mol Cell Cardiol 48, 246-253.

Sampson KJ, Iyer V, Marks AR & Kass RS. (2010). A computational model of Purkinje fibre single cell electrophysiology: Implications for the Long QT syndrome. J Physiol