The main goal of this core is to identify a panel of surrogate protein markers measurable in human serum that, in combination with other clinical factors, predicts long-term dysfunction following mild TBI. A second goal is to use surrogate markers for axonal degeneration to promote studies of the underlying molecular mechanisms and provide further validation for experimental models used in this proposal. Thus far, no individual marker has consistently demonstrated the ability to predict long-term functional impairment following mild TBI. To identify new markers for TBI and develop a marker panel, my laboratory initiated the first global analysis of protein release from degenerating neurons. We identified 14-3-3(3, 14-3-3^, a hypophpsphorylated form of neurofilament H, a calpain-derived cleavage product of a-spectrin, and a caspase cleavage product of aspectrin as highly abundant neuron-enriched proteins released from dying neurons. The validity of this approach was established by immunodetection of these proteins in CSF and serum following TBI or cerebral ischemia in rats, as well as severe TBI or surgically-induced circulation arrest in humans. To extend this research to mild human TBI, the specific aims of the core are to: (1) determine relationships between surrogate marker protein release, sodium channel dysfunction and axonal degeneration in a neuronal culture model for axonal injury (Project 3);(2) analyze our novel surrogate marker panel in a pig model of mild TBI, and relate changes to axonal histopathology and sodium channel dysfunction (Project 2);(3) evaluate serum elevations for the same marker panel in mild human TBI, and compare their levels with cognitive, neurological, and radiological measures of dysfunction (Project 1). A surrogate marker-based method for the prognosis of mild TBI, along with a simple quantitative means of assessing experimental neuroprotective therapies, would have enormous benefit for the management and treatment of mild TBI.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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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
Smith, Douglas H; Stewart, William (2016) Tackling concussion, beyond Hollywood. Lancet Neurol 15:662-663
Stewart, William; Smith, Douglas H (2016) Time to be blunt about blast traumatic brain injury. Lancet Neurol 15:896-898
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