This proposal will investigate the hypothesis that cytoskeletal pathology caused by traumatic brain injury (TBI) contributes to sublethal and lethal neuronal damage induced by TBI in rodent injury models. We have obtained evidence that sublethal TBI induces a substantial, regionally restricted decrease in protein levels of an important cytoskeletal element, microtubule-associated protein 2 (MAP2). The data implicate abberant cytoskeletal processes, perhaps involving degradative mechanisms, in post-injury pathology. Cytoskeletal damage also contributes to the pathology of spinal cord injury and is implicated in the cellular mechanisms of diffuse axonal injury. These observations suggest that cytoskeletal disruption may be an important pathogenic mechanism of TBI and may provide a significant opportunity for therapeutic intervention. The OVERALL OBJECTIVE of this proposal is to systematically examine TBI-induced alterations in the protein composition of the neuronal cytoskeleton and to examine their relationship with sublethal and lethal neuronal damage and injury-induced neurobehavioral deficits. In this project we will employ quantitative Western blot and qualitative immunohistochemical analyses to a) investigate in situ alteration of cytoskeletal proteins induced by moderate and severe magnitudes of TBI; b) determine the relationship between cytoskeletal derangements in specific brain regions and injury histopathology; c) investigate the relationship between cytoskeletal changes and the time course of maintenance and recovery from behavioral deficits; d) examine putative activation of endogenous calpain; e) examine putative changes in synthetic pathways (mRNA) for cytoskeletal proteins; and f) explore the efficacy of hypothermia, MK-801 and antiprotease therapy in preventing cytoskeletal degradation and ameliorating neurobehavioral deficits. An important COROLLARY GOAL of this proposal is to map the neuronal topography of traumatic injury to neurons using selective subcellular markers. Because the cellular distribution of many cytoskeletal elements is strictly regulated, these proteins can be used as specific molecular markers which illustrate the neuronal topography of TBI. We have identified cytoskeletal changes which occur selectively in the somatodendritic region of hippocampal neurons, but which do not occur in the cortex. This anatomical localization suggests these changes may a) have important implications for neurological deficits associated with spatial memory; b) contribute to neuronal dysfunction following sublethal traumatic insults; and c) reflect topographically the response of neurons to traumatic insults. Although our model of moderate fluid percussion injury produces sublethal neuronal damage, these studies can be extended to a more severe cortical impact injury model to examine the effects of lethal traumatic injury. At more severe injury magnitudes, these cytoskeletal changes may also underlie pathological processes ultimately leading to neuronal death.
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