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jmccabe@usuhs.mil
Ph.D., The City University of New York, 1983
Brain Injury and Neuroprotection
The long range goals of the laboratory are to understand biological responses to cell stress and to develop treatment approaches that ameliorate some of the lasting effects of traumatic brain injury. Three CNS injury models are employed: fluid percussion injury, cerebral hypoperfusion from hemorrhagic shock, and exposure to neurotoxic agents. Several drugs are of interest for their potential as prophylactic pretreatments before potential brain injury or as treatments following brain injury, including mitochondrial potassium ATP channel openers, steroid hormones, beta-lactam antimicrobials, and drugs that affect the neurotransmitter, N-acetyl-aspartyl-glutamate, the most abundant neuropeptide in the central nervous system.
Among the biological processes that have a role in cell stress and injury, we have most recently focused on the impact of TBI and cerebral hypoperfusion upon ubiquitin-proteasome function; a critical cellular process for the elimination of damaged proteins and for protein turnover related to signal transduction. For this research we have examined changes in the expression of the E3 ubiquitin-ligase complex protein, Cullin-5, changes in the expression of the three genes encoding ubiquitin, and study of beta-subunit expression of the constitutive proteasome (β1, β2, β5), inducible immunoproteasomes (β1i, β2i, β5i) and the 11S proteasome activator, PA28".
Our laboratory investigates drugs that may be efficacious for neuroprotection and CNS repair following brain injury or stroke. Recent focus is on the mitochondrial potassium ATP channel opener, diazoxide, which is based on the view that this organelle has a vital role in cellular function and response to injury. As the cell's main energy supply site-and mediator of "decisions" regarding apoptosis-mitochondria are at the nexus for induction of injury and potentially useful changes in cytoprotection. Work has examined how treatment with diazoxide affects functional outcome and expression of heat shock protein genes in the CNS. We have also focused on evaluating the steroid, progesterone, and the mechanisms for how progesterone brings about its therapeutic effects, including changes in Bcl-2 proteins that mediate apoptosis. Emory University has initiated a Protect clinical trial related to the efficacy of progesterone for the treatment of traumatic brain injury in patients.
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