Isabelle Deschenes

Assistant Professor

Ph.D., Laval University, Quebec, Canada
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Molecular Mechanisms of Cardiac Arrhythmias

RESEARCH DESCRIPTION

The research interests of my laboratory relate to the molecular mechanisms of cardiac arrhythmias. Arrhythmias are a major cause of morbidity and mortality in the United States. 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 Syndrome, conduction disease, sudden infant death syndrome and Brugada Syndrome, which cause life threatening arrhythmias leading to sudden death. My interests focus more specifically on the cardiac sodium channel which is involved in multiple cardiac diseases, such as Brugada Syndrome, Long QT Syndrome type 3, sudden infant death syndrome, cardiac conduction defect and sinus node disease. Although mutations in the cardiac sodium channel are associated with arrhythmias, these diseases also display incomplete penetrance, a phenomenon in which an individual carries a disease causing mutation but is asymptomatic. We previously demonstrated that a patient with a Brugada Syndrome mutation was asymptomatic and protected against arrhythmias because she carried a common sodium channel polymorphism which restored normal function of the mutated channel. Polymorphisms have been implicated in physiology, pharmacology, and pathophysiology. While most contemporary studies of ion channels seek to characterize the functional effects of mutations linked to rare diseases, new roles for polymorphisms, common variations in DNA sequence, are emerging. Therefore this project focuses on understanding the role that sodium channel polymorphisms play in explaining the incomplete penetrance of sodium channel related arrhythmias. We are also developing gene therapy approaches using those polymorphisms to prevent sodium channel related arrhythmias. In addition, delineation of the molecular basis and mechanism of the cardiac sodium channel are essential for an accurate understanding of cardiac ventricular depolarization. To address this, my lab has developed a new approach to study the 3D structure of the sodium channel. For this project we combine the use of Fluorescence Resonance Energy Transfer (FRET) with patch-clamping to obtain a dynamic 3D map of the sodium channel under normal and pathological conditions. The experimental approaches used in my laboratory involve patch-clamping, FRET, molecular biology, protein chemistry and adenovirus production.

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