Mitochondrial Pathways in Epileptogenesis Following Traumatic Brain Injury
Abstract
Annually approximately three million Americans experience traumatic brain injury (TBI), putting them at an increased risk of developing epilepsy. TBI represents a major cause of death and permanent disability in the population. In addition, patients with TBI are at an increased risk of developing post-traumatic epilepsy (PTE). It’s been estimated that PTE cases account for approximately 20% of total epilepsy cases. Despite significant work to uncover mechanisms of that underly seizures in models of epilepsy, the use of these therapeutic avenues in treating epileptogenesis has been underwhelming. Unfortunately, treatments targeted at the processes to decrease the incidence of PTE have been largely unsuccessful. This proposal will investigate both regional and temporal differences in mitochondrial function that underly the progression of PTE following TBI. The mitochondria lay at the intersection of several pathways in energy production, cellular excitability, cell signaling, and cell death. Recently, there has been an increase in the interest in the role of bioenergetics in epilepsy as well as other neuronal disorders. Mitochondria play a vital role in the overall function of individual cells and the brain as a system, and a deeper understanding of how mitochondria are at the intersection of epileptogenesis may be critical for advancing current therapies for treating epilepsy. Our central hypothesis is that altered mitochondrial energetics, redox balance, and cell death pathways are compromised during the epileptogenesis process leading to PTE. This proposal uses novel approaches to investigate how key mitochondrial pathways are altered in an animal model of TBI. Our first aim will look at cellular respiration, reactive oxygen species, calcium flux, and mitochondrial membrane potential following TBI. Our second aim will investigate the role of the mitochondrial signaling and excitability in mice that develop PTE. Finally, we will investigate if the ketogenic diet represents a therapeutic target for preventing PTE. Our experiments are carefully designed to provide valuable insight into the regional and temporal changes that effect the brain following TBI. All three aims in this proposal have yet to be investigated in TBI, and our ability to provide both spatial and temporal resolution in these processes will likely lead to the discovery of potential therapeutic targets for further study. In addition, we have chosen dietary therapy as it has high potential to be useful in the field. The inclusion of the ketogenic diet as a potential therapeutic avenue in the third aim has the potential for quick translation should our results be positive. We’ve chosen to test different delivery timepoints to test effectiveness to further increase clinical translation. In addition to the ketogenic diet, our proposal has the potential to impact clinical outcomes, as novel therapeutic agents targeting the mitochondria are under active development and understanding the pathways involved in PTE can lead to a more targeted pharmacologic approach. The Principal Investigator’s participation in the Virtual P-TERC is also well suited for his career goals. Despite success in cardiovascular research, he has always maintained his interest in neuroscience and has a strong desire to pursue an active research career in PTE. His previous research experience in a lab with a focus on epilepsy has given him a strong foundation to build upon, and the team assembled in place will ensure his success in this endeavor. His participation in the P-TERC can only serve to further enhance his career goals, training, and chances of sustaining a well-funded PTE research program.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310334
Entities
People
- Chad Frasier
Organizations
- East Tennessee State University
- United States Army