EXCEED THE SPACE PROVIDED. Traumatic brain injury afflicts 2 million people each year in the United States, many of whom suffer persistent neurological disability as a result of diffuse axonal injury. Shearing or stretching of axons during traumatic brain injury initiates progressive axonal damage, ultimately leading to axotomy and neuronal death. Because traumatic injury most often causes delayed rather than immediate axotomy, the opportunity exists to intervene therapeutically prior to axotomy. To elucidate the cellular mechanisms underlying traumatic axonal injury and identify therapeutic targets, we will perform dynamic optic nerve stretch injury in mice, accurately replicating the biomechanics of injury experienced by axons in the human brain during traumatic injury. We propose to use this established model of central nervous system axonal injury to test our working hypothesis that activation of calpains after traumatic axonal injury causes microtubule damage and impairment of axonal transport which, unless reversed, will lead to axotomy and neuronal apoptosis.
In Aim 1, we will evaluate anterograde and retrograde fast axonal transport as a function of injury severity and establish the time course of transport impairment relative to axotomy.
In Aim 2, we will establish a mechanistic link between calpain activation and interruption of axonal transport via degradation of microtubule-related proteins.
In Aim 3, we will test our hypothesis that prolonged disruption of axonal transport in optic nerve axons leads to apoptosis of retinal ganglion cells (RGCs).
In Aim 4, we will use IGF-1 overexpressing mice and exogenous IGF-1 treatment to determine whether elevation of IGF-1 levels can reverse transport impairment after axonal injury by delaying RGC apoptosis and upregulating cytoskeletal protein synthesis. Because regeneration of central nervous system axons remains an elusive goal, it is vital to intervene in the pathologic cascade of traumatic axonal injury before axotomy occurs. The optic nerve stretch injury model allows correlations between axonal pathology and either mechanical injury parameters or the cell body response that are not currently possible in whole-brain axonal injury models. By exploiting these unique advantages, we hope to identify key mediators in axonal pathology and novel therapeutic strategies to effectively sustain the vulnerable neuron and repair axonal damage prior to axotomy. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS045131-04
Application #
7060613
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Kleitman, Naomi
Project Start
2002-12-15
Project End
2007-11-30
Budget Start
2005-02-01
Budget End
2005-11-30
Support Year
4
Fiscal Year
2005
Total Cost
$225,853
Indirect Cost
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Serbest, Gulyeter; Burkhardt, Matthew F; Siman, Robert et al. (2007) Temporal profiles of cytoskeletal protein loss following traumatic axonal injury in mice. Neurochem Res 32:2006-14
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Smith, Douglas H; Uryu, Kunihiro; Saatman, Kathryn E et al. (2003) Protein accumulation in traumatic brain injury. Neuromolecular Med 4:59-72