The objective of this Phase I feasibility study is to develop a sensitive biomarker for quantifying neuroprotectant drug efficacy in a rat model of traumatic brain injury (TBI). Currently, no widely accepted biochemical marker that quantifies neuronal injury in rat TBI models is available. We have previously shown that during axonal degeneration in humans, the brain cytoskeletal protein MAP-tau is cleaved. Our laboratory has developed a sensitive ELISA that specifically measures cleaved MAP-tau (C-tau) in human CSF following head injury. Using this ELISA, we have shown that brain C-tau levels increase in rats after sustaining cortical impact-induced TBI. By measuring lesion volumes, Scheff et al have previously demonstrated that cyclosporin A administration following TBI significantly ameliorates cortical damage in the cortical impact rat model. We hypothesize that C-tau is a reliable biomarker of TBI-induced neuronal injury in rats. We will test this hypothesis by determining if C-tau levels demonstrate a time-dependent increase after TBI and if a known neuroprotectant intervention, cyclosporin A, exerts expected effects on C-tau levels.
Our Specific Aims are:
Specific Aim 1 : Determine whether TBI results in a time-dependent increase in brain levels of C-tau. C-tau levels will be quantified by ELISA in TBI-affected and control brain regions and also in sham operated animals.
Specific Aim 2 : Determine if C-tau levels reliably quantify the effect of a known neuroprotectant intervention on TBI. The neuroprotective effect of cyclosporin A will be examined by administering either vehicle or cyclosporin A. C-tau levels will be quantified by ELISA at the time of maximum TBI-induced C-tau elevation determined in Specific Aim 1. C-tau levels will be compared as a function of neuroprotectant treatment.
| Sharma, Ramaswamy; Gow, Alexander (2007) Minimal role for caspase 12 in the unfolded protein response in oligodendrocytes in vivo. J Neurochem 101:889-97 |
| Gabbita, S Prasad; Scheff, Stephen W; Menard, Renee M et al. (2005) Cleaved-tau: a biomarker of neuronal damage after traumatic brain injury. J Neurotrauma 22:83-94 |
