Traumatic brain injury (TBI) results in long term debilitation for millions of Americans. A consistent feature of this pathology is traumatic axonal injury (TAI), diffuse in profile and challenging to study. To date, TAI etiology is best documented in large caliber, myelinated axons, which consistently exhibit plasmalemmal, cytoskeletal and mitochondria! pathology. From diagnostic imaging it is clear that the corpus callosum and other subcortical white matter tracts are vulnerable to TAI. These pathways contain both large myelinated and small unmyelinated axons, where fiber type is systematically associated with sensorimotor and associative cortices. Given that TBI induces long-term cognitive deficits, and that TAI in subcortical white matter is poorly understood, our recently published studies have explored the physiological and morphological response of corpus callosum axons to diffuse TBI. Those results show rapid evolution of TAI and greater vulnerability of unmyelinated fibers. In parallel, pilot studies we also find upregulation of extracellular matrix (ECM) proteins and their regulatory metalloproteinases (MMPs) with callosal TAI. Such observations are consistent with the fact that these proteins mediate axonal growth, myelination and fasciculation. Based upon this information, we propose to explore the role of MMP/ECM pathways during degenerative and recovery phases of TAI. We will test the hypothesis that MMP/ECM proteins influence the progression of white matter TAI following TBI and that their activation is regulated by fibrinolytic proteins which permeate the neuropil through breaches in the blood brain barrier. Using the callosal TAI model, we will document protein/mRNA expression of tenascin and phosphacan, ECM proteins known to be present in white matter, and MMPs 2, 3 and 9, known to modify ECM after injury. Temporal profile of MMP activity will be correlated with enzyme expression and screening for adhesion molecule binding partners of these proteins will be performed. Next, we will similarly assess the response of fibrinolytic pathway proteins tPA and plasminogen to callosal TAI. Finally, we will pharmacologically manipulate either fibrinolytic/MMP enzyme activity or degree of axonal protection after injury and test for cause/effect relationships between fibrinolytic/MMP molecules and axonal integrity using functional and morphological endpoints. These studies will establish the role of MMP/ECM proteins in TAI and provide new therapeutic targets forTBI.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Hicks, Ramona R
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Virginia Commonwealth University
Anatomy/Cell Biology
Schools of Medicine
United States
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Schurman, Lesley D; Smith, Terry L; Morales, Anthony J et al. (2017) Investigation of left and right lateral fluid percussion injury in C57BL6/J mice: In vivo functional consequences. Neurosci Lett 653:31-38
Powell, Melissa A; Black, Raiford T; Smith, Terry L et al. (2017) Mild Fluid Percussion Injury Induces Diffuse Axonal Damage and Reactive Synaptic Plasticity in the Mouse Olfactory Bulb. Neuroscience 371:106-118
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Phillips, Linda L; Chan, Julie L; Doperalski, Adele E et al. (2014) Time dependent integration of matrix metalloproteinases and their targeted substrates directs axonal sprouting and synaptogenesis following central nervous system injury. Neural Regen Res 9:362-76
Chan, Julie L; Reeves, Thomas M; Phillips, Linda L (2014) Osteopontin expression in acute immune response mediates hippocampal synaptogenesis and adaptive outcome following cortical brain injury. Exp Neurol 261:757-71
Reeves, Thomas M; Smith, Terry L; Williamson, Judy C et al. (2012) Unmyelinated axons show selective rostrocaudal pathology in the corpus callosum after traumatic brain injury. J Neuropathol Exp Neurol 71:198-210
Warren, Kelly M; Reeves, Thomas M; Phillips, Linda L (2012) MT5-MMP, ADAM-10, and N-cadherin act in concert to facilitate synapse reorganization after traumatic brain injury. J Neurotrauma 29:1922-40
Harris, Janna L; Reeves, Thomas M; Phillips, Linda L (2011) Phosphacan and receptor protein tyrosine phosphatase ýý expression mediates deafferentation-induced synaptogenesis. Hippocampus 21:81-92
Colley, Beverly S; Phillips, Linda L; Reeves, Thomas M (2010) The effects of cyclosporin-A on axonal conduction deficits following traumatic brain injury in adult rats. Exp Neurol 224:241-51

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