Sudden cardiac death is a major health concern in most nations around the world including the United States with an incidence of >300,000 persons/year. The genetic background of an individual can play a significant role in predisposing a person to developing an arrhythmia. In fact, mutations in the cardiac sodium, potassium and calcium channels are responsible for inherited clinical phenotypes, including Long QT (LQTS) and Brugada Syndrome (BrS), which cause life threatening arrhythmias leading to sudden death. The main research focus of my lab resides in understanding the molecular basis of inherited cardiac arrhythmias. Throughout my career, my studies have been centered on the fundamental molecules that underlie the electrical function of the heart, including the channel that is responsible for the initiation of the action potential, the sodium channel. I utilize molecular and electrophysiological techniques to study the structure-function of the sodium channel and have also applied insights from our fundamental studies to more translational research that is essential to understanding the role cardiac ion channels plays in inherited cardiac arrhythmias. During these efforts, I have discovered novel and unexpected roles for sodium channel polymorphisms acting as disease modifying genes which explained the genotype-phenotype discordance seen in several LQTS and BrS families. This work will provide the basis for several areas of investigation over the next 5 years. I will still be studying the molecular mechanisms of arrhythmias but we propose an alternative approach that involves the derivation of induced pluripotent stem cells from family carriers with divergent LQTS or BrS expressivity or genotype-negative BrS patients and differentiation of these stems cells into cardiac myocytes. Carrier-specific cardiomyocytes will be fully characterized at the cell- and electrophysiological level followed later on by targeted sequencing of mRNA or protein-coding subsequences, which requires only about 5% effort compared to whole genome sequencing. The projects outlined below, mainly structural in nature, will represent the focus for the Established Investigator Award, allowing my lab to pursue exciting areas of interest that are not funded by other mechanisms. Together, these projects should identify new genes involved in BrS and provide new insights into the molecular mechanisms of genotype-phenotype discordance seen in families with inherited cardiac arrhythmias.
|Program type||Established Investigator Award|
|Effective start/end date||01/01/2012 → 12/31/2016|