# Methylomics of pediatric traumatic brain injury and neurobehavioral recovery

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $615,627

## Abstract

PROJECT SUMMARY
Traumatic brain injury (TBI) is the leading cause of acquired disability in children. The evidence available to
guide TBI management is disproportionately low relative to its medical and societal burden. Recovery from TBI
is determined by the interaction of a multitude of dynamic biological, psychosocial, and therapeutic factors.
DNA methylation (DNAm; the methylome) is a major epigenetic regulator of gene expression that responds
dynamically to an individual’s internal (e.g., tissue insult) and external (e.g., psychosocial adversity)
environment. Initial preclinical and adult clinical studies show differential DNAm both acutely and months after
TBI; however, little is known regarding pediatric TBI. Because the methylome is dynamic over time and
responsive to both internal and external factors associated with TBI recovery, we hypothesize that the
methylome confers risk or protective effects on long-term neurobehavioral recovery through the regulation of
genes involved in the brain’s response to TBI. Therefore, interrogation of the methylome could reveal critical
information about the biologic complexity underlying recovery, with significant potential for improving future
clinical management of pediatric TBI. To further interrogate the methylome as an untapped source of biologic
complexity underlying recovery from pediatric TBI, we will generate methylome-wide DNAm data from an
ongoing longitudinal study of children aged 3-18 years with complicated mild to severe TBI or orthopedic injury
(OI; comparison group). Our two-tiered analytic approach will involve: Tier 1. Comprehensive examination of
brain derived-neurotrophic factor (BDNF) DNAm (~55 DNAm sites), grounded in our strong preliminary data;
and Tier 2. Unbiased discovery-based analysis of the entire methylome (>935,000 sites), revealing the most
significant methylomic signals for future targeted biomarker research. Both Tiers will be examined within each
of the following Specific Aims: (1) Determine the association between pediatric TBI and acute DNAm; (2)
Identify associations between acute DNAm and long-term neurobehavioral outcomes; (3) Identify associations
between acute DNAm and disparities in neurobehavioral outcomes as a function of psychosocial adversity;
and (4) Explore associations between longitudinal DNAm and neurobehavioral recovery. Exemplifying rigor
and reproducibility, our approach includes analysis of a discovery cohort (235 TBI, 179 OI) followed by
replication in an independent cohort (105 TBI, 105 OI). Finally, we will conduct clinical feasibility testing to
ensure that only the most rigorous, reproducible, and clinically translatable findings advance for further
scientific inquiry. The overall impact of this work will be to advance the field of pediatric TBI towards precision
medicine and health equity through an improved understanding of the biologic complexity underlying recovery
and its intersection with psychosocial adversity; revealing biologic signa...

## Key facts

- **NIH application ID:** 10980135
- **Project number:** 1R01NS135492-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Amery Treble-Barna
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $615,627
- **Award type:** 1
- **Project period:** 2024-05-15 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980135

## Citation

> US National Institutes of Health, RePORTER application 10980135, Methylomics of pediatric traumatic brain injury and neurobehavioral recovery (1R01NS135492-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10980135. Licensed CC0.

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