Download TBI Abstract - Stacey Lee, PhD

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Transcript
NEUROPROTECTIVE EFFICACY OF PURINERGIC RECEPTOR
AGONISTS IN VITRO AND IN WHOLE ANIMALS AFTER
TRAUMATIC BRAIN INJURY
Stacey Lee, PhD and Jim Lechleiter, PhD
Department of Cellular and Structural Biology, UTHSCSA
Traumatic brain injuries (TBIs) are the cause of over 30% of injury-related deaths
in the United States. Both civilians and military personnel are at risk for TBIs from blunt
force or blast trauma. Side effects of TBI can range from dizziness, nausea, headaches,
concentration problems, memory impairment, mood disorders, and seizures. On a
molecular level, there are two phases of injury after a TBI. The primary phase is the
initial physical trauma. The secondary phase occurs within the following days of the
injury leading to edema, excitotoxicity, neuronal damage, cell death, inflammatory
responses, and blood-brain barrier dysfunction. Currently, there is no FDA-approved
treatment for TBI despite an urgent need for one. The goal of our work is to characterize
novel therapeutic compounds to mitigate brain damage induced by TBI. The project
aims to mitigate injury responses by improving astrocyte energy metabolism.
Astrocytes are essential for maintaining neuronal function and homeostasis in the
brain. They provide neurons with metabolic support, modulate synaptic transmission,
and aid in repair after injury. Previous research from the lab has shown that enhancing
mitochondrial metabolism in astrocytes protects neurons from oxidative stress.
Specifically, treating astrocytes with a purinergic receptor agonist enhances their ATP
production and decreases cytotoxic edema and reactive gliosis. We hypothesize that
enhancing astrocyte metabolic activity with these agonists will protect the brain against
TBI-induced damage.
We have two mechanisms for generating TBIs: a pneumatic impact device that
generates a closed controlled cortical impact, or blunt trauma, and an air-driven shock
tube simulating an IED explosion, or blast trauma. Using these two methods, we will
asses the ability of our compounds to reduce astrocyte injury response, injury size,
edema, inflammatory response, behavior, and seizures. We predict agonist treatment
after injury will prevent the secondary damage responses from exacerbating the injury
and lead to an improved outcome on a molecular and behavioral level. This work is
supported by the Department of Defense grant number W81XWH-15-1-0283.