Translational Modeling of Brain Injury Rehabilitation to Maximize Recovery.

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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 plus BCAAs for improving recovery trajectory over a six-month period (also with Veteran-relevant delayed treatment). Previous studies suggest that exercise and BCAA therapies share common mechanisms of action and effects, and therefore I will effectively be testing the overarching hypothesis that enhancing neurotrophic signaling and improving sleep quality after injury can improve cognitive recovery and reduce ARAS pathology following moderate TBI. Beyond the advancements that this project will provide for our mission to maximize functional recovery from brain injury in our Veterans, I will be gathering invaluable knowledge and expertise from a dedicated, world-class mentorship team and carving a niche for my future career as an independent VA investigator. Due to the swine model and the community of researchers gathered around it, the CMC-VAMC and University of Pennsylvania are at the epicenter of translational TBI research. The greatest environment in the world to achieve my research goals in TBI rehabilitation is within this community, and I intend to become an integral member throughout my career. I will achieve independence through this Career Development Award and provide considerable return on investment through a highly productive VA research career.