Heart disease remains the leading cause of death in the United States and other developed countries. Half of these deaths occur suddenly, typically from ventricular tachyarrhythmias that arise in the setting of acute ischemia, acquired heart disease or inherited syndromes including channelopathies and cardiomyopathies. The specialized cardiac conduction system (CCS) comprises a heterogeneous network of cells that orchestrate the initiation and propagation of a wave of electrical excitation throughout the myocardium. Purkinje cells comprise the most distal component of the CCS and substantial, but indirect experimental data has accumulated supporting the concept that Purkinje cells play a key mechanistic role triggering a broad range of life-threatening ventricular arrhythmias. However, major gaps in our understanding of Purkinje cell biology have prevented this realization from being translated into novel anti-arrhythmic strategies. Through our recent identification of contactin-2, a novel cell adhesion molecule expressed in the conduction system, we have established new tools to identify, isolate and characterize murine Purkinje cells. Using these tools, we propose a series of studies to investigate contactin-2 dependent regulation of Purkinje network development, the regulation of cardiac electrophysiology by contactin-2 in normal and diseased hearts, and contactin-2 dependent mechanisms regulating pathologic remodeling in Purkinje cells.
PROJECT NARRATIVE Heart disease is the leading cause of death in the United States and other developed countries and almost half of these deaths occur suddenly from heart rhythm abnormalities. Our research is directed toward understanding the mechanisms responsible for these lethal arrhythmias and identifying potential new therapeutic targets.
|Shekhar, Akshay; Lin, Xianming; Liu, Fang-Yu et al. (2016) Transcription factor ETV1 is essential for rapid conduction in the heart. J Clin Invest 126:4444-4459|
|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; Cerrone, Marina; Morley, Gregory et al. (2015) Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias. J Clin Invest 125:403-12|
|Maass, Karen; Shekhar, Akshay; Lu, Jia et al. (2015) Isolation and characterization of embryonic stem cell-derived cardiac Purkinje cells. Stem Cells 33:1102-12|
|Iyer, Vivek; Roman-Campos, Danilo; Sampson, Kevin J et al. (2015) Purkinje Cells as Sources of Arrhythmias in Long QT Syndrome Type 3. Sci Rep 5:13287|
|Tsai, Su-Yi; Maass, Karen; Lu, Jia et al. (2015) Efficient Generation of Cardiac Purkinje Cells from ESCs by Activating cAMP Signaling. Stem Cell Reports 4:1089-102|
|Lin, Xianming; O'Malley, Heather; Chen, Chunling et al. (2015) Scn1b deletion leads to increased tetrodotoxin-sensitive sodium current, altered intracellular calcium homeostasis and arrhythmias in murine hearts. J Physiol 593:1389-407|
|Kim, Eugene E; Shekhar, Akshay; Lu, Jia et al. (2014) PCP4 regulates Purkinje cell excitability and cardiac rhythmicity. J Clin Invest 124:5027-36|
|Dun, Wen; Wright, Patrick; Danilo Jr, Peter et al. (2014) SAP97 and cortactin remodeling in arrhythmogenic Purkinje cells. PLoS One 9:e106830|
|Park, David S; Fishman, Glenn I (2014) Nav-igating through a complex landscape: SCN10A and cardiac conduction. J Clin Invest 124:1460-2|
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