Ovine model system for alcohol related birth defects

描述（由申请人提供）：尽管为教育妇女在怀孕期间不要饮酒做出了巨大努力，但胎儿酒精谱系障碍的发病率并未下降，因此了解产前酒精暴露导致神经发育损伤的机制非常重要，以便制定预防和改善策略。在本提案中，我们将利用完善的绵羊模型的独特优势来研究酒精导致脑损伤的基本机制，并开始探索保护策略。我们已经报道，酒精会导致母体和胎儿酸血症以及母体谷氨酰胺和谷氨酰胺相关代谢物的减少。我们假设酒精介导的酸血症会减少胎儿谷氨酰胺和谷氨酰胺相关代谢物，这会导致或促进氧化应激和脑损伤的升高。在具体目标 1 中，我们假设酒精会引起母体和胎儿酸中毒，从而导致胎儿中谷氨酰胺及其含氮代谢物浓度发生变化。实验 1 在长期使用仪器的羔羊胎儿中测试这一假设，以响应急性酒精或酸血症操作，并将确定母体谷氨酰胺是否会阻止代谢物浓度的变化。在具体目标 2 中，我们假设在相当于人类大脑发育的第三个三个月期间，产前接触酒精会导致酸血症、胎儿谷氨酰胺减少和氧化应激增加。实验2a将确定酒精或酸血症是否会改变母体和胎儿区室中以及胎儿大脑中的谷氨酰胺及其代谢物的浓度和通量，以及母体谷氨酰胺施用是否可以防止这些变化。实验 2b 将测试在相当于人类大脑发育的妊娠晚期，酒精介导的 pH 值和谷氨酰胺下降是否会导致氧化应激增加，以及母体谷氨酰胺是否具有预防作用。具体目标 3 假设母体施用谷氨酰胺将预防胎儿因妊娠第三个月等效酒精暴露而造成的脑损伤（实验 3 测试该假设）。由于已知酒精通过多种机制发挥作用，我们预测谷氨酰胺将在很大程度上但不能完全预防脑损伤，这些发现将使我们处于开发实用、组合、营养预防的绝佳位置，这也是 NIAAA 战略计划中的既定目标。公共卫生相关性：教育未能显着降低胎儿酒精综合症的发病率，因此了解产前酒精暴露导致神经发育损害的机制非常重要，以便制定预防和改善策略。在本提案中，我们测试了几个假设，这些假设将解释酒精如何造成这种损害，并将测试基于这些假设的营养预防措施。这项研究涉及国家酗酒和酒精滥用研究所战略计划中的既定目标。

DESCRIPTION (provided by applicant): Despite significant efforts to educate women to not drink during pregnancy, the incidence of Fetal Alcohol Spectrum Disorders has not declined making it important to obtain understanding of the mechanisms by which prenatal alcohol exposure causes neurodevelopmental damage in order to develop preventative and ameliorative strategies. In this proposal, we will exploit the unique advantages of the well established sheep model to investigate basic mechanisms by which alcohol causes brain injury and to begin exploring protective strategies. We have reported that alcohol causes maternal and fetal acidemia and reductions in maternal glutamine and glutamine-related metabolites. We hypothesize that alcohol mediated acidemia decreases fetal glutamine and glutamine-related metabolites and that this results in, or contributes to, elevations of oxidative stress and brain injury. In Specific Aim 1, we hypothesize that alcohol induces maternal and fetal acidosis that results in altered concentrations of glutamine and its nitrogenous metabolites in the fetus. Experiment 1 tests this hypothesis in chronically instrumented lamb fetuses in response to acute alcohol or acidemia manipulations and will determine if maternal glutamine will prevent the changes in metabolite concentrations. In Specific Aim 2, we hypothesize that prenatal alcohol exposure throughout the 3rd trimester equivalent of human brain development acts by causing acidemia, reductions in fetal glutamine and increases in oxidative stress. Experiment 2a will determine if alcohol or acidemia alters concentrations of glutamine and its metabolites in, and flux between, maternal and fetal compartments and across the fetal brain and if maternal glutamine administration prevents these changes. Experiment 2b will test whether the alcohol mediated decreases in pH and glutamine throughout the third trimester equivalent of human brain development results in increases in oxidative stress and if maternal glutamine is preventative. Specific aim 3 hypothesizes that maternal glutamine administration will prevent the fetal brain injury in response to 3rd trimester equivalent alcohol exposure (Experiment 3 tests this hypotheis). Because alcohol is known to act through more than one mechanism, we predict that glutamine will substantially but not completely prevent brain injury and that these findings will place us in an excellent position to develop a practical, combinatory, nutritional prevention, a stated goal in the NIAAA strategic plan. PUBLIC HEALTH RELEVANCE: 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. In this proposal we test several hypotheses that would explain how alcohol causes this damage and will test a nutritional prevention based on the on these hypotheses. This research addresses a stated goal in the National Institute on Alcoholism and Alcohol Abuse strategic plan.