Although altered metabolism is rapidly emerging as a key feature of epilepsies, it has not been systematically investigated in any genetic form of pediatric epilepsy. Dravet syndrome (DS), a catastrophic childhood epilepsy associated with de novo mutations in a voltage-activated sodium channel, Nav1.1 is one of the most common genetic epilepsies. DS patients suffer with intractable early-life seizures, and debilitating comorbidities. Energy metabolism in comorbidities associated with DS remain virtually unexplored. To address this unmet need, recent collaborative research in our two laboratories revealed decreased glycolytic and oxygen consumption rates in a validated zebrafish model of DS i.e., scn1Lab mutants. This was accompanied by downregulation of key enzymes, pck1 and pck2, in the gluconeogenesis pathway. Here, we hypothesize that energy disruption occurs in DS due to glucose dysregulation resulting in seizures and/or comorbidities. The following aims are proposed to test this hypothesis.
Aim 1 will determine if pharmacological inhibition of pck1 and/or pck2 phenocopies metabolic and behavioral deficits in wildtype zebrafish.
Aim 2 will determine if pharmacological manipulation of pck1 and/or pck2 is therapeutic in scn1Lab mutant zebrafish. These studies promise to provide a mechanistic explanation of the metabolic defects observed in DS and could suggest novel avenues for therapeutic intervention.

Public Health Relevance

The proposed research will provide novel insight into malfunction of energy producing pathways in pediatric genetic epilepsy and suggest innovative metabolic treatments for controlling pediatric seizures and behavioral impairment.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD102071-01
Application #
9990441
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ren, Zhaoxia
Project Start
2020-06-01
Project End
2025-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045