Kass Lab

Research Overview

Dr. Kass' 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.

About Dr. Kass

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.