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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD040848-03
Application #
6615618
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Vitkovic, Ljubisa
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
3
Fiscal Year
2003
Total Cost
$124,686
Indirect Cost
Name
Children's Hosp Pittsburgh/Upmc Health Sys
Department
Type
DUNS #
044304145
City
Pittsburgh
State
PA
Country
United States
Zip Code
15224
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Lai, Yichen; Hickey, Robert W; Chen, Yaming et al. (2008) Autophagy is increased after traumatic brain injury in mice and is partially inhibited by the antioxidant gamma-glutamylcysteinyl ethyl ester. J Cereb Blood Flow Metab 28:540-50
Li, Wenjin; Wu, Shasha; Hickey, Robert W et al. (2008) Neuronal cyclooxygenase-2 activity and prostaglandins PGE2, PGD2, and PGF2 alpha exacerbate hypoxic neuronal injury in neuron-enriched primary culture. Neurochem Res 33:490-9
Hickey, Robert W; Adelson, P David; Johnnides, Michael J et al. (2007) Cyclooxygenase-2 activity following traumatic brain injury in the developing rat. Pediatr Res 62:271-6
Hickey, Robert W; Painter, Michael J (2006) Brain injury from cardiac arrest in children. Neurol Clin 24:147-58, viii
Manole, Mioara D; Hickey, Robert W (2006) Preterminal gasping and effects on the cardiac function. Crit Care Med 34:S438-41
Manole, Mioara D; Hickey, Robert W; Momoi, Nobuo et al. (2006) Preterminal gasping during hypoxic cardiac arrest increases cardiac function in immature rats. Pediatr Res 60:174-9
Kawaguchi, Kenji; Hickey, Robert W; Rose, Marie E et al. (2005) Cyclooxygenase-2 expression is induced in rat brain after kainate-induced seizures and promotes neuronal death in CA3 hippocampus. Brain Res 1050:130-7
Gangula, P R R; Lanlua, P; Bukoski, R D et al. (2004) Mesenteric arterial relaxation to calcitonin gene-related peptide is increased during pregnancy and by sex steroid hormones. Biol Reprod 71:1739-45

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