Axonal damage is a hallmark of diffuse brain injuries, and is considered by many as a nearly universalconsequence of traumatic brain injury. Recent evidence shows that unmyelinated axons are particularlyvulnerable to damage in DAI. In this project, we study the mciromechanical aspects of axonal injury tounmyelinated axons. Our long term objective to study when sodium channel proteolysis occurs in axonsafter mild TBI, determine the mechanism(s) that regulate this channel proteolysis, and to evaluate theeffectivenes of different biomarkers to evaluate this form of axonal damage.
Our specific aims are to:
Aim 1 : To measure the strain rate sensitive threshold for sodium channel mechanoactivation followingaxonal stretch injury in vitro, determining the pathway(s) that contribute to both immediate and sustainedstretch-induced increases in axoplasmic calcium,Aim 2: To determine the thresholds and timecourse of sodium channel proteolysis after axonal stretch,assess if this proteolysis is mediated by calpain activation and linked to a specific stretch-induced calciumpathway, and evaluate if the proteolysis can be reduced using delayed treatments.
Aim 3 : To determine the threshold and time course of a delayed increase in membrane permeability afteraxonal stretch injury, examine if this permeability changes is responsive to delayed treatments, and to test ifthis permeability change leads to a detectable release of 'biomarkers' for detecting axonal injury in vitro.Our overall hypotheses are that (a) sodium channel mechanoactivation occurs during mild stretch injury tounmyelinated axons, (b) sodium channel proteolysis is calpain mediated, (c) the primary pathway(s) forsustained calcium elevation in axons after stretch is a critical target in controlling sodium channel proteolysisafter axonal injury.Relevance: One common type of injury in head injured patients is the swelling and disconnection of axonsthroughout many brain regions. We will study how this injury occurs, evaluate if we can treat this injury, andwill assess if there specific biomarkers that can serve as prognostic indicators of axonal degeneration.
| 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 |
| 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 |
| 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 |
| 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 |
| Levin, Harvey S; Diaz-Arrastia, Ramon R (2015) Diagnosis, prognosis, and clinical management of mild traumatic brain injury. Lancet Neurol 14:506-17 |
| 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 |
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