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.
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