This renewal application represents a highly collaborative, multidisciplinary approach to elucidate molecular mechanisms of injury to the immature brain caused by neonatal hypoxic/ischemia (H/l), utilizing neuroprotective and neurogenic interventions that can be clinically translated. The goals are to (1) identify mechanisms of H/l injury to the developing brain, (2) identify the effects of resuscitative hyperoxia on injury mechanisms, neurogenesis, and long-term outcome, (3) develop clinically-realistic interventions that are effective both alone and in combination, and (4) characterize gender-dependent differences in mechanisms and responses to intervention. Based on progress made during the previous grant period and on results generated by the new project investigators, the investigators hypothesize that H/l injury is caused by complex interactions among oxidative stress, disruption of lipid raft-protein interactions, metabolic failure subsequent to acute mitochondrial injury, and attenuation of GABAergic stimulation. They also hypothesize that optimal neuroprotection following H/l can be achieved by avoiding unnecessary hyperoxia, stimulating aerobic energy metabolism by administration of acetyl-L-carnitine, protecting lipid rafts, genomic post-conditioning against secondary oxidative stress by administration of sulforaphane, and inhibition of apoptosis and stimulation of neurogenesis by administration of estradiol and enhancement of GABA. Project I focuses on mitochondrial mechanisms of metabolic failure and apoptosis, and on the molecular basis for neuroprotection by sulforaphane. Project II focuses on early and long-term alterations in neuronal and glial energy metabolism, neurotransmitter biosynthesis, and the molecular basis for neuroprotection by acetyl-L-carnitine. Studies include serial in vivo imaging, 31P and 1H-MR, and ex vivo 13C-NMR spectroscopy. Project III focuses on neurogenesis, its regulation by depolarizing GABA, and how estradiol can promote neurogenesis and neuronal survival. Project IV focuses on the effects of H/l on lipid raft-protein interactions and function of the LI cell adhesion molecule, a key protein involved in neurite outgrowth, neuronal plasticity, and signal transduction pathways. All projects will use the neonatal rat H/l model, supported by Core B, and a common O2 and glucose deprivation model using cultured cortical or hippocampal neurons at different stages of in vitro development. All projects are also tied together by the common theme of oxidative stress, the effects of gender on mechanisms and outcome, as well as optimization of neurologic outcome by protection against cell death, protecting mitochondrial proteins, preserving signal transduction, or promotion of neurogenesis.
The significance of the proposed studies is that they will determine the relationships among oxidative stress, metabolic dysfunction, gender, and both neurodegeneration and neuroregeneration in the immature brain. The investigative team will also jointly explore clinically feasible neuroprotective interventions that eventually could be used to minimize the neurologic impairment and mental retardation caused by acute brain injury in neonates and children.
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