Project Details
Early Career
Status: Funded - Closed
The role of fibrin in inflammation, neuron survival, and behavior after traumatic brain injury
Terry Dean, MD, PhD
Summary
BACKGROUND: Approximately 630,000 children in the US sustain a traumatic brain injury (TBI) at least severe enough to warrant care in an emergency room setting (~700 per 100,000 children), which is the major contributor to the 12,000 pediatric deaths each year from unintentional injuries. Although TBI is the main contributor to accident-related deaths in children, the single most common cause of pediatric mortality, and TBI survivors are at high risk for lifelong neurologic disability, there are no targeted therapies to prevent or treat the disease. GAP: TBI has been shown to induce persistent fibrin deposition in human brains as well as inflammation and neurodegeneration, however, no studies have examined whether these phenomena are mechanistically related, and whether blocking it can improve outcomes. HYPOTHESIS: We hypothesize that fibrin and microglial activation will share similar distributions following TBI in humans and an animal model. Furthermore, we hypothesize that genetic and pharmacologic disruption of the fibrin-microglia interaction will decrease neuroinflammation, neuronal loss, and behavioral deficits. METHODS: After confirming the colocalization of fibrin and microglia following TBI in humans and mice, we will compare the effects of genetic and pharmacologic disruptions of the fibrin-microglia interaction on neuroinflammation and neuronal loss via methods in immunohistochemistry as well as on neurologic deficits via thorough behavioral testing. RESULTS: Pending IMPACT: By using genetic and pharmacologic tools, we suspect that we will decrease neuroinflammation and neuronal loss at a cellular level, as well as provide protection at an organismal level. If successful, this project will significantly advance our aim to pursue clinical trials of the first targeted therapeutic for a profoundly significant childhood health problem. Website Link: https://akassogloulab.org