Prenatal alcohol exposure causes neurodevelopmental injuries through multimechanistic pathways that are still poorly understood. Only through the identification of those mechanisms will it be possible to develop preventative and ameliorative strategies. It is hypothesized that alterations in maternal/fetal pH, oxidative stress and altered amino acid metabolism are mechanistically important in causing the neurodevelopmental damage. Correction of these deficits through maternal administration of glutamine, a key intermediary in several processes disrupted by alcohol, could provide protection from alcohol induced neurodevelopmental damage. Thus glutamine could prove to be a successful and plausible nutritional intervention strategy for alcohol mediated neurodevelopmental disorders, fulfilling a current NIAAA strategic initiative. These experiments will exploit the unique advantages of the now well established sheep model, where the feto-maternal unit is intact throughout the entire equivalent of human fetal brain development. The sheep model allows simultaneous fetal and maternal sampling, a necessity in the investigation of the proposed mechanism(s) and nutritional intervention strategy. The first specific aim of this proposal is to evaluate the alcohol induced changes in fetal glutamine, glutamine-related metabolites, and other amino acids in response to both an acute and chronic alcohol exposure paradigm. Acute exposure preliminary data revealed a significant decrease in fetal glutamine as well as multiple other amino acids, which has serious implications for fetal growth, acid-base homeostasis, defense against oxidative stress (brain injury) and fetal programming. These decreases and their consequences could be a major mechanism of alcohol induced neurodevelopmental damage. The second specific aim is to quantify indices of oxidative stress in the fetal brain. Preliminary data demonstrated regional differences in oxidative stress among brain regions in response to prenatal alcohol exposure. This selectivity correlates with the neuronal loss observed in response to chronic binge alcohol exposure in the sheep model. Alcohol mediated decreases in glutamine may worsen damage by impairing defense against oxidative stress, since glutamine is a precursor for glutathione. The third specific aim is to test the protective abilities of glutamine supplementation to prevent the changes characterized in specific aim 1 and 2 and document any protection from alcohol induced neuronal loss. It will also provide data to characterize changes occurring with chronic versus acute alcohol exposure and whether or not any compensatory change occurs. Dr. Wilson left private veterinary practice to enter the field of medical research and has fulfilled approximately 75% of the requirements towards a PhD in biomedical science. Her long term career goal is to become an independent investigator in the field of alcohol research. She has formed a committee of five mentors to maximize her learning potential and gain an advantage in approaching a field of study that involves many different organ systems and areas of research expertise. The training, resources, collaborative relationships and data pool that will result from this proposal will put her in a position to develop new ideas and projects and a funding stream to support them. The training and experience in both nutrition and alcohol research combined with her veterinary expertise and background will uniquely equip her to split off in a direction that is fundamentally different from that of her mentoring team and develop a highly independent and productive research career in the future.
The failure of education to significantly reduce the incidence of Fetal Alcohol Syndrome has made it important to obtain understanding of the mechanisms by which prenatal alcohol exposure causes neurodevelopmental damage in order to develop preventative and ameliorative strategies. This proposal tests hypotheses that would explain how alcohol causes this damage and will test a nutritional prevention based on these hypotheses. This research addresses a stated goal in the NIAAA strategic plan.
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