PROJECT SUMMARY The overall goal of this proposal is to test whether the plasma levels of Osteopontin (OPN), a highly stable phosphoprotein secreted by macrophages/activated microglia, predict the severity and functional outcomes in pediatric traumatic brain injury (TBI). This hypothesis derives from pilot data in >60 children suggesting that OPN may be a more sensitive biomarker in pediatric TBI than glial fibrillary acidic protein (GFAP). In this proposal, we will perform a prospective study with 175 children to determine the prognostic value of plasma OPN, either alone or in combination with two other biomarkers (GFAP or Ubiquitin C-terminal Hydrolase L1, UCH-L1) for the clinical course and 6-month functional outcomes in pediatric TBI. A simple blood-based biomarker that correlates with the severity and progression of TBI would enable appropriate triage in acute treatment, clinical trial stratification, and follow-up rehabilitation plan. Aim 1: To correlate the trajectory of plasma OPN, GFAP, UCH-L1 level in 72h of TBI-onset with the severity and progression of brain damage in pediatric patients. We will perform a prospective study at Children’s Healthcare of Atlanta (CHOA) to collect blood samples from 175 children (25 controls and 30 mild TBI at admission; 30 moderate TBI and 90 severe TBI at 0, 24, 48, and 72h of hospitalization) to measure OPN, GFAP, and UCH-L1 levels. We plan to examine its relationship to the severity and progression of brain injury, including GCS, Injury Severity Score (ISS), mortality, intracranial lesions on CT, external ventricular drainage (EVD), intracranial pressure (ICP), and the days requiring ventilator or ICU support. We hypothesize that the peak plasma levels of OPN within 72h of admission outperform those of GFAP and UCH-L1 to show stronger correlations with the severity and progression of pediatric TBI. Aim 2: To test the predictive value of plasma OPN for the functional outcomes at 6 months after severe pediatric TBI. We will track the participants and evaluate their functional status at 6 months post injury using the Extended Glasgow Outcome Scale (GOSE), WeeFIM Score (Functional Independence Measure for children), and behavioral and emotional measures. Next, we will use regression analysis to compare the strength of correlation of the peak plasma OPN, GFAP, and UCH-L1 levels within 72 h post- TBI with the above functional measures. We hypothesize that the peak plasma OPN levels, either alone or combined with the GFAP or UCH-L1 level, will predict the functional outcomes in children with severe TBI.

PUBLIC HEALTH RELEVANCE STATEMENT (Narrative): TBI is a major cause of death and disability in the United States, responsible for near 30% of all injury-related deaths and according to the Center for Disease Control and Prevention, children ages 0-14 are at greater risk. A simple and reliable surrogate biomarker that predicts the clinical course and functional outcomes in pediatric TBI could have enormous implications. The proposed study may help to establish a novel blood biomarker to assist clinical management of pediatric TBI.