Temporal Dynamics of Astrocytic Activation and Function in Post-Traumatic Epilepsy (PTE) Genesis and Progression
Abstract
Objectives and Rationale Post-traumatic epilepsy (PTE) is when someone experiences recurring and unprovoked seizures after sustaining a traumatic brain injury (TBI). PTE is a common and serious complication of TBI. There are no U.S. Food and Drug Administration (FDA)-approved medicines for prevention or treatment of PTE beyond current antiepileptic drugs, and there are no blood tests based on biomarkers for PTE. The disease course from TBI to PTE is not well understood, which further hampers the development of novel biomarkers and therapeutic targets. This project aims to identify specific changes in astrocytes, which are special star-shaped cells in the central nervous system, and how they contribute to the transition from TBI to PTE. Based on evidence we gathered in our previously funded Department of Defense grant, which revealed molecules associated with astrocytes are activated in mice with PTE, compared to mice without PTE, we believe that astrocyte signatures have a key role in the progression from TBI to PTE. We think that by clarifying how these signatures impact TBI/PTE, we can identify novel PTE-associated molecules for future blood tests and therapeutics for PTE. We will do this by integrating various neuroimaging and large-scale molecular analyses to characterize the temporal dynamics of astrocytic signatures both before and after PTE starts, in a mouse model and in patient samples. Applicability and Impact This project will ultimately lead to the identification of TBI patients who are at risk of developing PTE. It will provide markers for early detection and monitoring of PTE, and therapeutic targets to help prevent the progression or improve symptoms once they develop. The target population includes combat Soldiers and Veterans who may experience TBI. The outcomes of this project could lead to the prevention or improvement of the disease course from TBI to PTE, and therefore could help military and civilian victims of TBI/PTE alike. Identifying combat casualties with novel blood tests for PTE-associated biomarkers, followed by treatment with novel therapeutics for PTE, will improve care, management, and disposition for PTE, including return-to-duty decisions. To progress to clinical research, the following outcomes will be achieved in this project: (1) various neuroimaging and large-scale molecular measures that underly astrocytic signatures associated with the presence or absence of PTE in different brain regions and (2) a defined time course for astrocytic signatures that are predictive of PTE in blood samples from TBI patients. This project will lead to a greater understanding of the key astrocytic signatures underlying TBI progression towards PTE, which will advance PTE research, as currently little is known of the mechanisms and markers of TBI-induced PTE. The biomarkers and therapeutic targets identified in this project can be used to improve patient care after someone has experienced TBI by identifying their risk of developing PTE, monitoring their progression from TBI to PTE, and treating them before they develop PTE, as well as treating them to after they develop PTE to reduce the severity of PTE. In conclusion, this project will help to reduce the burden of PTE on military TBI casualties – improving the quality of life for PTE patients and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310184
Entities
People
- Lauren C Harte-Hargrove
Organizations
- United States Army