There is a growing recognition that mild traumatic brain injury (mTBI) or concussion is a major health issue, with over 2 million cases each year in the United States. Moreover, there is increasing concern that there may be a period of vulnerability after one mTBI, during which time a second mTBI may induce greatly exaggerated pathophysiological effects. We have used a multidisciplinary approach to generate experimental in vitro and in vivo models that replicate the mechanical loading conditions of mTBI in humans. With these models, we have recently identified that diffuse axonal injury (DAI) is a key pathology of single mTBI. In addition, we have shown that microtubule damage as well as dysregulation of sodium channels on axons following traumatic injury are watershed events contributing to axonal vulnerability, dysfunction and degeneration. Moreover, we have generated promising preliminary data indicating the utility of novel neuroimaging and serum biomarkers for the detection of brain damage in mTBI. Here, we propose to use these models to 1) investigate novel diagnostic techniques to evaluate axonal pathology in single and repetitive mTBI, and 2) explore the mechanistic roles of axonal cytoskeletal changes that may induce enhanced vulnerability that accounts for exacerbated damage with a repeat mTBI. Innovation: Success of the proposed studies could lead to 1) new diagnostic criteria to identify mTBI pathologies, 2) identify new pathologies and mechanisms of single and repetitive mTBI, and 3) reveal new therapeutic targets.

Public Health Relevance

Mild traumatic brain injury (mTBI), or 'concussion,' is now recognized as a major health issue. We propose to use our newly established in vitro and in vivo models to investigate new diagnostic techniques for mTBI and explore the role of diffuse axonal injury in single and repetitive mTBI. Success of the proposed studies could improve mTBI diagnosis, identify new mechanisms and reveal new therapeutic targets for mTBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS092398-02
Application #
9012120
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bellgowan, Patrick S F
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Dollé, Jean-Pierre; Jaye, Andrew; Anderson, Stewart A et al. (2018) Newfound sex differences in axonal structure underlie differential outcomes from in vitro traumatic axonal injury. Exp Neurol 300:121-134
Johnson, Victoria E; Weber, Maura T; Xiao, Rui et al. (2018) Mechanical disruption of the blood-brain barrier following experimental concussion. Acta Neuropathol 135:711-726
Nagata, Katsuhiro; Kumasaka, Kenichiro; Browne, Kevin D et al. (2016) Unfractionated heparin after TBI reduces in vivo cerebrovascular inflammation, brain edema and accelerates cognitive recovery. J Trauma Acute Care Surg 81:1088-1094
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
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
Li, Shengjie; Eisenstadt, Rachel; Kumasaka, Kenichiro et al. (2016) Does enoxaparin interfere with HMGB1 signaling after TBI? A potential mechanism for reduced cerebral edema and neurologic recovery. J Trauma Acute Care Surg 80:381-7; discussion 387-9
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
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
Li, Shengjie; Marks, Joshua A; Eisenstadt, Rachel et al. (2015) Enoxaparin ameliorates post-traumatic brain injury edema and neurologic recovery, reducing cerebral leukocyte endothelial interactions and vessel permeability in vivo. J Trauma Acute Care Surg 79:78-84

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