The voltage-gated sodium channel (Na-channel) is a central component of cardiac electrogenesis. Dysfunction of this channel is a critical mediator of arrhythmias that cause sudden cardiac death in common cardiac pathologies (ischemia and heart failure), and in genetic disorders. Rare as well as common genetic variants in SCN5A, encoding the poreforming Na-channel subunit NaV1.5, have been strongly associated with life-threatening arrhythmias. Yet, insight into Na-channel physiology is limited, and effective therapies targeting Na-channel dysfunction are virtually non-existent. !! !! Our central purpose is to develop a highly interactive network of investigators working on a fundamental problem through multi-disciplinary and complementary expertise. This synergistic environment will deliver the best scientific output and the highest quality multidisciplinary training of emerging young scientists. !! !! The overarching research objectives are to:!! (1)! Define the differential composition and function of the Na-channel complex in the working ventricular muscle versus the specialized conduction system of the heart and across discrete domains of the respective myocytes.!! (2)! Characterize the molecular machinery and the dynamics of delivery of Na-channels to their selected subdomains. !! (3) ! Identify and validate novel small molecules that can modify Na-channel function. !! !! The research design follows a sequence, from discovery and validation of targets, to mechanistic studies and assessment of their potential for translation into therapeutics. Overall, we will use this knowledge as a foundation for future advances in the prevention and treatment of cardiac arrhythmias that cause sudden cardiac death.!!
|Effective start/end date||1/1/18 → 12/31/22|
- Leducq Foundation (17CVD02 Signed 11/07/17)
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