# Translational Modeling of Brain Injury Rehabilitation to Maximize Recovery.

> **NIH VA IK2** · PHILADELPHIA VA MEDICAL CENTER · 2024 · —

## Abstract

The motivating force driving me to build an independent research enterprise has been my personal desire to
maximize functional recovery after traumatic brain injury (TBI). Experiences in my life have solidified this
research goal as one of primary purpose, and my career trajectory and accomplishments through adversity
stand as evidence of my devotion to that purpose and ability to acheive it. This mission brought me to the
Philadelphia CMC VA Medical Center (CMC-VAMC), where I have found that my own research goals align
perfectly with those of the Rehabilitation R&D (RR&D) Service and the needs of our Veterans. To make the
greatest impact on TBI rehabilitation, I will utilize a unique large animal model to accurately replicate the
mechanisms and manifestations of human TBI: the swine rotational acceleration system applied to great effect
by my mentor, D. Kacy Cullen, PhD, and other researchers in his Center for Neurotrauma, Neurodegeneration,
and Restoration at the CMC-VAMC and University of Pennsylvania. In addition to diffuse axonal injury, this
model results in damage to the ascending reticular activating system (ARAS) as observed in moderate TBI in
humans, leading to temporary loss of consciousness and lasting effects on sleep, fatigue, and cognition that are
major factors during recovery from TBI. Due to their small brain size, our commonly used rodent models
cannot be used to reproduce these aspects of the human injury or their manifestations, as the damage is a
product of rotational acceleration and brain mass. In this project I propose to build on the swine model,
extending beyond the acute injury period following moderate TBI to establish the first translational model of
moderate TBI Rehabilitation and Recovery at long-term time points most relevant for our Veteran population.
Such a high-fidelity preclinical model will provide the rigor and control necessary to directly test the efficacy of
individual ingredients of rehabilitation therapies (e.g. diet, exercise) and conduct detailed mechanistic
investigations to inform adjustments to existing therapies and development of new therapies that improve
efficacy. I will christen this vessel of bidirectional translation with a blinded, randomized investigation of the
efficacy and mechanisms of action of dietary branched-chain amino acid (BCAA) therapy for enhancing
cognitive recovery over a three-month study period (including investigation of Veteran-relevant delayed therapy
administration). Our studies will benefit greatly from clinically-relevant advanced neuroimaging, a gamut of
clinically-inspired neurobehavioral and neurological testing, extensive histopathological and
immunohistochemical analyses, and high-resolution post-mortem diffusion tensor imaging with anisotropy,
diffusivity, and tractography to quantify changes in brain connectivity that are a hallmark of human TBI. I will
also utilize this model to test the mechanisms and efficacy of regular exercise rehabilitation or exercise p...

## Key facts

- **NIH application ID:** 10793479
- **Project number:** 5IK2RX003376-04
- **Recipient organization:** PHILADELPHIA VA MEDICAL CENTER
- **Principal Investigator:** John Charles O'Donnell
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10793479

## Citation

> US National Institutes of Health, RePORTER application 10793479, Translational Modeling of Brain Injury Rehabilitation to Maximize Recovery. (5IK2RX003376-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10793479. Licensed CC0.

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