There is a transient period of increased sensitivity to hypoxic-ischemic and excitatory amino acid (EAA)-mediated brain injury that parallels the development of synaptic connectivity and EAA-receptor maturation in developing brain. In rodents, this period of increased sensitivity to brain injury occurs between 1-3 wk following birth. The inducible isoform of cyclooxygenase (COX-2) is developmentally regulated gene that is induced by synaptic activity and down-regulated by EAA antagonists. Thus, neuronal COX-2 production is greatest during the period of maximal synaptic proliferation coinciding with the period of increased vulnerability to hypoxic-ischemic and excitotoxic brain injury that occurs from 1-3 wk following birth. Recently, COX-2 has been identified as contributing to the development of ischemic brain injury in mature rodents. These observations suggest that COX-2 may be an unrecognized mediator of developmentally regulated susceptibility to hypoxic-ischemic and excitotoxic brain injury in immature brain. The ability of hypoxia-ischemia and EAA toxicity to induce COX-2 expression in the developing brain and the effect of COX-2 inhibition upon injury to the developing brain has not been investigated. Accordingly, The candidate proposes to test the hypothesis the induction of COX-2 exacerbates hypoxic-ischemic and EAA-mediated injury in the developing brain. In addition, the candidate will use tissue culture and gene knock-out technology to investigate a potential mechanism of COX-2 toxicity. Namely, he will investigate the possibility that COX-2 and nitric oxide synthase (NOS) synergistically contribute to the formation of the highly toxic reactive oxygen species peroxynitrite. This is an attractive line of inquiry because neuronal NOS is a developmentally regulated gene with temporal profile of expression mirroring COX-2 expression and because it will expose the candidate to experiments using tissue culture and gene knock-out technology. The candidate s long-term objective is to develop into an independent clinician scientist with a complete battery of research skills and the capability of mentoring other clinician scientists. A Mentored Clinical Scientist Development Award will allow continued access to excellent mentorship and will increase the time available for attaining new research skills. The proposed experiments take advantage of on-campus expertise with two molecules of significant scientific interest - COX and NOS. The proposed experiments provide the candidate with access to a rich variety of contemporary molecule biology tools that will promote his development as a clinician scientist in Pediatric Emergency Medicine while facilitating an in depth examination of the mechanisms involved in COX-2 neurotoxicity. Understanding these mechanisms is of potential clinical importance because treatments that are commonly used in critically injured infants and children (e.g., NSAIDS, steroids, etc.) can influence COX-2 production and isoform-specific COX-2 inhibitors have recently become clinically available.
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