Friday, November 22, 2024
11/22/2024
Project Summary Dravet Syndrome (DS) is a catastrophic pediatric epilepsy that largely arises from loss-of-function mutations in sodium channel genes. Overlapping neuronal and cardiac expression patterns of mutant sodium channels are proposed to underlie the pathophysiology of a number of genetic diseases that exhibit both epileptic and cardiac phenotypes. The risk of sudden death in epilepsy patients is twenty four times greater than the general population. Despite advances in recent years to understand the mechanisms of Sudden Unexpected Death in Epilepsy (SUDEP), it has remained elusive. Proposed mechanisms of SUDEP have implicated seizure-induced apnea, pulmonary edema, dysregulation of cerebral circulation, autonomic dysfunction, or cardiac arrhythmias. Besides being the powerhouse of the cell, the mitochondria is responsible for long term ionic balance in the cell and compromised mitochondrial function may precede cardiac arrhythmias and epileptic events. This project seeks to uncover novel mechanisms by which cardiac excitability is altered due to compromised mitochondrial energetics in Dravet Syndrome (DS) models, a form of epilepsy with a high incidence of SUDEP. My central hypothesis is that compromised mitochondrial energetics and ionic homeostasis predisposes DS patients to cardiac arrhythmias, seizures, and SUDEP-like events. I plan to test this hypothesis through the following two specific aims: 1) we will determine if mitochondria play a role in ionic homeostasis in mouse models of DS. This aim will test the hypothesis that DS mice have an impaired ability to buffer changes in cytosolic Na+ and Ca2+ during times of stress. Using multiple models, we will determine the role that the mitochondria plays in long-term cellular ionic balance. 2) We will determine if mitochondrial energetics and the ability to match ATP supply with demand is compromised in DS mice. This aim will test the hypothesis that mitochondrial energetic of DS mice have increased reactive oxygen species (ROS) production and a decreased ability match ATP supply with demand. Experiments will investigate the ability of mitochondria in our DS mouse models to generate ATP at the whole organ, isolated cell, and organelle level. The significance of this project is that it fills a major void in understanding the mechanism of SUDEP in DS and results from the proposed experiments have the potential to lead to new therapeutic treatments in DS. While this grant focuses on the role of DS mutations, due to the high incidence of SUDEP, it is our hope that these results may be applicable to other genetic and non-genetic epilepsies that will be the focus of future projects. The proposed studies will provide valuable insight to the field and may lead to the discovery of several potential therapeutic targets for DS. The mitochondria represent an ideal target to investigate, as there is growing interest in the mitochondrial mechanisms of arrhythmogenesis and novel drugs may soon be available to test in epilepsy models.
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