Overview
Research in our laboratory is focused on identifying genetic factors that contribute to Developmental and Epileptic Encephalopathies, severe childhood epilepsies with developmental consequences. We use genetically engineered mouse models for genomic, transcriptomic, physiological and pharmacological studies aimed at understanding how genetic variations contribute to the disease pathophysiology. The overarching goal is to translate this knowledge into precision therapies for childhood epilepsy syndromes.
Developmental and Epileptic Encephalopathies Under Investigation
Dravet syndrome
The major goal of this research is to identify genes that contribute to severity of Dravet syndrome, a catastrophic infant-onset epilepsy that includes developmental delays, high mortality risk, and seizures that are difficult to treat with available medicines. We identify genes that modify disease severity and mortality risk using genetic approaches in combination with bulk and single cell transcriptomics. Identifying modifier genes will provide insight into the underlying causes of epilepsy and suggest novel therapeutic strategies for improved treatment of human patients. Therapeutic candidates identified in our genetic studies are tested in our translationally-validated preclinical model of Dravet syndrome using a variety of pharmacologic and RNA-based approaches.
SCN2A-Associated Epilepsy
Disruption of brain development can result in a number of neurodevelopmental disorders, including epilepsy, developmental delay, intellectual disability, and autism spectrum disorder. A major contributor to these disorders are mutations in the SCN2A gene, which is critical for proper cellular communication in the developing brain. We are working to understand how mutations in this gene lead to a wide-spectrum of neurodevelopmental disorders. We have generated mouse models with different mutations and are comparing neurobehavioral, physiological and pharmacological phenotypes, which is coupled with parallel mechanistic studies of mutation effects at the molecular, cellular and circuit levels.
KCNB1-Associated Epilepsy
Severe childhood epilepsies are often caused by mutations in genes critical for brain development and neuronal communication. Understanding how genetic mutations lead to epilepsy and co-associated neurodevelopmental problems can improve outcomes for this disease. Mutations in KCNB1 cause co-associated epilepsy and neurodevelopmental delay. We are characterizing the functional effects of KCNB1 human variants on protein function using high throughput electrophysiology and flow cytometry. In addition, we made mouse models carrying mutations with different mechanisms of action, and are currently comparing cellular, physiological, and pharmacologic phenotypes, as well as the effect of genetic background on severity.