Role for kinase activation in transport impairment after traumatic axonal injury

Grants and Contracts Details


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
Effective start/end date1/15/101/14/16


  • KY Spinal Cord and Head Injury Research Trust: $299,463.00


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