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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS056202-05
Application #
8377470
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$249,441
Indirect Cost
$47,634
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Chen, H Isaac; Wolf, John A; Smith, Douglas H (2017) Multichannel activity propagation across an engineered axon network. J Neural Eng 14:026016
Stewart, William; Smith, Douglas H (2016) Time to be blunt about blast traumatic brain injury. Lancet Neurol 15:896-898
Wilde, Elisabeth A; Hunter, Jill V; Li, Xiaoqi et al. (2016) Chronic Effects of Boxing: Diffusion Tensor Imaging and Cognitive Findings. J Neurotrauma 33:672-80
Ali, Zarina S; Johnson, Victoria E; Stewart, William et al. (2016) Neuropathological Characteristics of Brachial Plexus Avulsion Injury With and Without Concomitant Spinal Cord Injury. J Neuropathol Exp Neurol 75:69-85
Hay, Jennifer; Johnson, Victoria E; Smith, Douglas H et al. (2016) Chronic Traumatic Encephalopathy: The Neuropathological Legacy of Traumatic Brain Injury. Annu Rev Pathol 11:21-45
Smith, Douglas H; Stewart, William (2016) Tackling concussion, beyond Hollywood. Lancet Neurol 15:662-663
Johnson, Victoria E; Stewart, William; Weber, Maura T et al. (2016) SNTF immunostaining reveals previously undetected axonal pathology in traumatic brain injury. Acta Neuropathol 131:115-35
Patel, Tapan P; Man, Karen; Firestein, Bonnie L et al. (2015) Automated quantification of neuronal networks and single-cell calcium dynamics using calcium imaging. J Neurosci Methods 243:26-38
Levin, Harvey S; Diaz-Arrastia, Ramon R (2015) Diagnosis, prognosis, and clinical management of mild traumatic brain injury. Lancet Neurol 14:506-17
Rabinowitz, Amanda R; Li, Xiaoqi; McCauley, Stephen R et al. (2015) Prevalence and Predictors of Poor Recovery from Mild Traumatic Brain Injury. J Neurotrauma 32:1488-96

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