- ADJUNCT ASSOCIATE PROFESSOR Medicine
- ADJUNCT ASSOCIATE PROFESSOR Structural and Chemical Biology
We are addressing a number of fundamental questions related to the molecular pathogenesis of cardiovascular diseases. A major focus of our studies is a greater understanding of cardiac electrophysiology and uncovering how altered cardiac excitability leads to heart rhythm disturbances, especially ventricular tachycardia and sudden cardiac death. We utilize a multi-disciplinary approach employing biochemical, biophysical, molecular genetic, electrophysiological and gene targeting/transgenic strategies. Much of our effort is directed toward increased understanding of the regulation and function of the connexin family of gap junction channel genes. We are trying to elucidate how gap junction channel dysfunction results in conduction disturbances and promotes cardiac arrhythmogenesis.
Our hope is that pharmacological manipulation of gap junctional activity will ultimately lead to improved therapy for cardiac arrhythmogenesis. Our laboratory is also interested in understanding mechanisms regulating cardiac contractile performance, both normally and in the diseased heart. Presently, we are focusing on a recently discovered protein named sorcin, which regulates intracellular calcium release and thereby influences cardiac excitation-contraction coupling. We are using both in vitro molecular and cell biological approaches, in combination with gain and loss-of-function strategies in the mouse to elucidate the functional role of sorcin. We anticipate that modulation of sorcin function in the heart will evolve as a novel therapeutic target for regulation of cardiac contractility.
Finally, our laboratory has invested substantial effort to develop novel mouse models of human cardiovascular disease, using conditional transgenic and gene targeting approaches. We have recently developed a conditional transgenic system to reversibly control both the temporal and spatial expression of selected target transgenes in the mouse heart, using tetracycline-responsive promoters. We are also utilizing Cre/lox technology to conditionally inactivate endogeneous genes in a tissue-restricted and temporally regulated manner. Together, these approaches are providing us with powerful new mouse models of acquired cardiovascular diseases.
Top row, left to right: Zhaowei Ai, Avi Fischer, Glenn Fishman, David Gutstein Bottom row: Afshan Ismat, Jie Zhang, Stacey Rentschler, Hui Jin, Marian Meyers
Figure 1. Optical Images of Normal and Arrhythmogenic Mouse Hearts. Epicardial activation patterns in isolated-perfused mouse hearts were visualized with voltage-sensitive fluorescent dyes. Compared to control hearts (A), myopathic hearts show varying degrees of conduction defects (B-D), including areas with very slow conduction (E) that serve as obstacles for reentrant ventricular tachycardia (from Lee et al, PNAS, 1998).
Spray DC, Vink MJ, Fishman G. Major cell biological issues and strategies in discontinuous conduction. In: Spooner PM, Joyner RW, Jalife J, editors. Discontinuous Cardiac Conduction. Mt. Kisco, NY, Futura Publishing Company, Inc; 1997. pp185-201.
Srinivas M, Costa M, Gao Y, Fort A, Fishman GI, Spray DC. Voltage dependence of macroscopic and unitary currents of gap junction channels formed by mouse connexin50 expressed in rat neuroblastoma cells. J Physiol (Lond) 1999; 517(Pt 3): 673-689.
Wickenden A, Lee P, Sah R, Huang Q, Fishman GI, Backx P. Targeted expression of a Kv4.2 dominant-negative potassium channel subunit in the mouse heart. Circ Res 1999; 85: 1067-1076.
Redfern CH, Degtyarev MY, Kwa AT, Salomonis N, Cotte N, Nanevicz T, Fidelman N, Desai K, Vranizan K, Lee EK, Coward P, Shah N, Warrington J, Fishman GI, Bernstein D, Baker AJ, Conklin BR. Conditional expression of a Gi-coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy. Proc Natl Acad Sci U S A 2000; 97: 4826-4831.
Ai Z, Fischer A, Spray DC, Brown AM, Fishman GI. Wnt-1 Regulation of Connexin43 in Cardiac Myocyte. J Clin Invest 2000; 105: 161-171.
Kagan A, Yu Z, Fishman GI, McDonald TV. The dominant-negative LQT2 mutation A561V reduces wildtype HERG expression. J Biol Chem 2000; 275: 11241-11248.
Fishman G, McDonald TV. Gene transfer of membrane channel proteins. In: Zipes DP, Jalife J, editors. Cardiac electrophysiology: from cell to bedside. Philadelphia, PA, W.B. Saunders Company; 2000.
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Dr.Fishman is not currently required to report Industry relationships.
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