We hypothesize that 1) a key pathologic substrate of mild traumatic brain injury (MTBI) is diffuse axonal injury (DAI), 2) DAI in MTBI can be detected non-invasively, and 3) and the pathophysiology of DAI includes the dysregulation of voltage gated sodium channels (NaChs) on axons following trauma. In parallel studies with MTBI patient evaluation performed in Project 1, we will use a pig model of MTBI to determine the sensitivity of non-invasive techniques to elucidate brain pathology, using advanced magnetic resonance imaging techniques and a panel of surrogate protein markers. We will also evaluate functional outcome after MTBI in the pig using a new functional assessment paradigm. Importantly, the pig model allows us to correlate non-invasive findings with histopathology. The data from the pig can then be extrapolated to the non-invasive data from MTBI patients in Project 1. To test our hypothesis of posttraumatic axonal NaCh dysfunction we will use a stepwise in vitro to in vivo approach. Using an in vitro model of axon stretch injury, we will determine the thresholds of axon trauma that trigger a deleterious feed-forward pathway of NaCh dysfunction, including acute calcium influx and NaCh proteolysis followed by hyperexpression of NaChs on axons. These efforts will be supported by in vitro studies in Project 3 examining the micromechanics of axonal trauma and mechanisms of proteolysis. We will examine the potential clinical relevance of feed-forward pathway of NaCh dysregulation using the pig MTBI model. In particular, we will evaluate acute regional changes in axonal NaChs linked with immediate loss of consciousness and axon degeneration. We will also examine potential hyperexpression of NaChs on white matter axons in relation to long-term axon degeneration. Success of the proposed project could lead to new diagnostic criteria to identify the pathologies and mechanisms in MTBI and provide targets for new therapeutic interventions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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University of Pennsylvania
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Chen, H Isaac; Wolf, John A; Smith, Douglas H (2017) Multichannel activity propagation across an engineered axon network. J Neural Eng 14:026016
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