DAVID HOSACK PROFESSOR OF PHARMACOLOGY (IN THE CENTER FOR NEUROBIOLOGY AND BEHAVIOR) AND CHAIRMAN
Regulation of ion channel expression in normal and genetically-altered cardiac cells: gene-targeted pharmacology of inherited cardiac arrhythmias.
The research in the Kass lab focuses on the regulation and expression of ion channel proteins in normal and genetically altered heart. A major focus of this laboratory is the relationship between inherited mutations in cardiac ion channels and the initiation of fatal cardiac events in carriers of these gene defects. The goal of this work is to determine the molecular basis of these fatal arrhythmias in order (1) to develop improved diagnostic approaches and (2) to develop a specific pharmaco-genetic approach to the management of these disturbances. In order to approach these goals, our laboratory integrates investigation of mammalian cells that have been transiently-transfected with cDNA encoding. Patch clamp analysis of wild type and mutant forms of human cardiac ion channel gene products allow us to determine specific disease-induced changes in channel function and unique pharmacological properties that the mutations may confer. Second, we work with genetically-altered mice in order to determine possible interactions between these mutant ion channels and cellular signaling systems such as the b-adrenergic signaling cascade. Our laboratory interacts closely with an international consortium of clinical colleagues who identify novel gene mutations carried by patients that they treat and then, in turn, apply the pharmacological information we gain at the cellular level to tests and treatment directly in humans. We are presently concentrating our efforts on the long QT syndrome and the Brugadas' Syndrome, two diseases that have been shown to be causally linked to mutations in cardiac ion channels. Our laboratory is fully equipped to carry out the electrophysiology and molecular biological procedures needed for this work. Representative publications follow.
1. An R-H, Heath BM, Higgins JP, Koch WJ, Lefkowitz RJ and Kass RS: b2-adrenergic receptor overexpression in the developing mouse heart: evidence for targeted modulation of ion channels. J. Physiol. 516: 19-30, 1999. Abstract PDF File
2. An RH, Wang XL, Kerem B, Benhorin J, Medina A, Goldmit M and Kass RS: Novel LQT-3 mutation affects Na+ channel activity through interactions between a- and b1-subunits. Circ. Res. 83:141-146, 1998. Abstract PDF File
3. Heath BM, Xia J, Dong E, An RH, Brooks A, Liang C, Federof HJ and Kass RS: Overexpression of nerve growth factor in the heart alters ion channel activity and b-adrenergic signaling in an adult transgenic mouse. J. Physiol. 512:779-791, 1998. Abstract PDF File
5. Kass RS: Genetically induced reduction in small currents has major impact. Circulation 96:1720-1721, 1997.