This renewal application represents a multidisciplinary approach to determine factors that regulate transport, metabolic compartmentation, energy production, synthesis of neurotransmitters and endogenous effectors of neurotransmitter receptors, and cell death. The studies in Project I will focus on mechanisms and role of glutamate formed from glutamine in the interstitial space of the brain. Data suggest that the mechanisms leading to the formation of glutamate in the extracellular space of the brain are different in the normal unstressed brain and in the traumatized brain, such as occur following an episode of hypoxia/ischemia. It is hypothesized that phosphate-dependent glutaminase and gamma-glutamyl transpeptidase are involved. A hypoxia/ischemia rat model and a knock-out mouse models will be used in the study. Project II will address the interrelation among energy metabolism, kynurenic acid synthesis, and glutamatergic mechanisms during development. Kynurenic acid is a broad-spectrum antagonist of the ionotropic excitatory amino acid receptors and preferentially blocks the glycine co-agonist site of NMDA receptors at low concentrations. Therefore, kynurenic acid may influence neuronal vulnerability to excitatory insults by functioning as a modulator of glutamatergic neurotransmission. A knock-out mouse model lacking the enzyme for kynurenine biosynthesis has enhanced sensitivity to excitotoxicity. Studies in Project III address the hypothesis that impairment in energy metabolism, neuronal/glial metabolic trafficking, and neurotransmitter biosynthesis may result in long-term damage to developing brain that result in ongoing cellular damage even after the initial insult has ceased. It will also assess the hypothesis that it is crucial for the brain to maintain the proper balance of production and utilization of lactate, since this monocarboxylic acid is a substrate for developing brain, and possibly for neurons in adult brain. Biochemical and NMR studies will be addressed in animal models of hypoxia/ischemia and hypoglycemia. Studies in Project IV will follow up on the important finding that brain mitochondria from immature rats exhibit resistance to bioenergetic failure caused by exposure to high levels of Ca++ in a hypoxia/ischemia model. These studies may lead to the development of targeted neuroprotective interventions in neonates and children.
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