Sudden cardiac death from ventricular tachyarrhythmias results in as many as 450,000 deaths annually in the United States. Several lines of investigation suggest that abnormal expression and function of cardiac gap junction channels, a process termed gap junction remodeling (GJR), plays a key mechanistic role in the development of these lethal cardiac arrhythmias. In particular, we recently demonstrated that genetically engineered mice with widespread loss of connexin43 (Cx43), the major cardiac gap junction channel protein, developed spontaneous ventricular tachycardia, culminating in arrhythmic death. However, the pathologic remodeling of gap junctions that is observed in response to a wide spectrum of cardiovascular diseases is undoubtedly a reflection of aberrant connexin regulation, rather than a complete loss of transcription as is produced with """"""""knockout"""""""" strategies. Accordingly, we now propose to expand upon our initial observations and develop increasingly sophisticated in vivo murine models that will allow us to explore the mechanisms through which aberrant gap junction regulation contributes to arrhythmogenesis. Based upon a large body of evidence, we will focus especially upon post-translational phosphorylation of Cx43, defining its role in normal physiology and during the process of gap junction remodeling associated with various cardiomyopathic stimuli.
Our specific aims are: 1) to characterize the significance of casein kinase-15 (CK16)-dependent phosphorylation of Cx43 during normal physiology and in response to cardiomyopathic stimuli associated with GJR using gene-targeted murine models; 2) to characterize the regulation of Cx43 by CK16 using a transgenic approach, and 3) to characterize the consequences of Cx43 tyrosine phosphorylation during normal physiology and in response to cardiomyopathic stimuli associated with GJR using gene-targeted murine models. The long-term goal of our work is to identify molecular targets that are amenable to anti- arrhythmic therapy, ultimating decreasing the public health burden associated with cardiovascular disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL082727-02
Application #
7407544
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Przywara, Dennis
Project Start
2007-04-15
Project End
2012-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$405,250
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Fishman, Glenn I (2017) Drug-Induced Arrhythmias, Precision Medicine, and Small Data. Circ Arrhythm Electrophysiol 10:
Park, David S; Shekhar, Akshay; Marra, Christopher et al. (2016) Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure. Nat Commun 7:12966
Park, David S; Fishman, Glenn I (2014) Nav-igating through a complex landscape: SCN10A and cardiac conduction. J Clin Invest 124:1460-2
Kim, Eugene; Fishman, Glenn I (2013) Designer gap junctions that prevent cardiac arrhythmias. Trends Cardiovasc Med 23:33-8
Stewart, Michael K G; Gong, Xiang-Qun; Barr, Kevin J et al. (2013) The severity of mammary gland developmental defects is linked to the overall functional status of Cx43 as revealed by genetically modified mice. Biochem J 449:401-13
Danielson, Laura S; Park, David S; Rotllan, Noemi et al. (2013) Cardiovascular dysregulation of miR-17-92 causes a lethal hypertrophic cardiomyopathy and arrhythmogenesis. FASEB J 27:1460-7
Remo, Benjamin F; Giovannone, Steven; Fishman, Glenn I (2012) Connexin43 cardiac gap junction remodeling: lessons from genetically engineered murine models. J Membr Biol 245:275-81
Lorentz, R; Shao, Q; Huang, T et al. (2012) Characterization of gap junction proteins in the bladder of Cx43 mutant mouse models of oculodentodigital dysplasia. J Membr Biol 245:345-55
Park, David S; Fishman, Glenn I (2012) Forever young: induced pluripotent stem cells as models of inherited arrhythmias. Circulation 125:3055-6
Giovannone, Steven; Remo, Benjamin F; Fishman, Glenn I (2012) Channeling diversity: gap junction expression in the heart. Heart Rhythm 9:1159-62

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