Grants and Contracts Details
Description
Traumatic axonal injury (TAl) is a common pathological finding in traumatic brain injury (TBI) and a significant
contributor to posttraumatic morbidity. TAl results in impaired axonal transport, which may be mediated in part
by cytoskeletal proteolysis. However, it is becoming increasingly clear that TAl presents with multiple
phenotypes which may involve different intracellular mechanisms and require unique treatment strategies.
Activation of c-Jun N-terminal kinase (JNK) and glycogen synthase kinase 313(GSK3f3) have been implicated
in anterograde axonal transport dysfunction through the disruption of kinesin binding. In Aim 1, we test the
hypothesis that TAl leads to JNK and GSK3j3 activation, by localizing phosphorylated JNK and GSK3f3 to
anterogradely labeled axonal swellings in a model of optic nerve stretch that produces diffusely scattered
axonal injury in a population of CNS axons with a defined directionality. We will then test the efficacy of
specific JNK and GSK3j3 inhibitors to attenuate axonal transport dysfunction. This will provide the first
causal link between JNK and GSK3f3 and trauma-induced transport impairment, identifying a new therapeutic
target for white matter injury. Recent studies link calpain proteases with activation of JNK and GSK3f3,
suggesting that calpains may serve as an upstream therapeutic target. In Aim 2, we administer a selective
calpain inhibitor to test the hypothesis that activation of calpains after TAl results in transport
impairment through increased activity of JNK and GSK3j3. While we propose that activation of axonal
JNK initiates transport dysfunction, pJNK may also act as a retrograde injury signal. After nerve ligation, pJNK
is preferentially transported in the retrograde direction, via an interaction with the retrograde motor complex
facilitated by JNK-interacting protein (JIP). In Aim 3, we hypothesize that TAl triggers the retrograde
transport of pJNK and JIP to the soma, where pJNK phosphorylates and activates c-Jun, a transcription
factor that is associated with cell death and regeneration responses. The ability of JNK inhibition to attenuate
retinal ganglion cell c-Jun and caspase-3 activation will be quantified, providing new insights into the poorly
understood relationship between the cell body response and TAL This proposal investigates a novel
mechanism underlying axonal dysfunction after trauma. Our findings will have implications for developing
treatment strategies targeting white matter injury in TBI and spinal cord injury.
2
Status | Finished |
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Effective start/end date | 1/15/10 → 1/14/16 |
Funding
- KY Spinal Cord and Head Injury Research Trust: $299,463.00
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