Ovine model system for alcohol related birth defects

描述（由申请人提供）：尽管在教育妇女不要在怀孕期间饮酒方面做出了重大努力，但胎儿酒精谱系障碍的发病率并没有下降，因此了解产前酒精暴露导致神经发育损害的机制，以制定预防和改善策略非常重要。在本提案中，我们将利用成熟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。我们已经报道了酒精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降低了胎儿谷氨酰胺和谷氨酰胺相关代谢物，这导致或促成了氧化应激和脑损伤的升高。在特异性目的1中，我们假设酒精诱导母体和胎儿酸中毒，从而导致胎儿体内谷氨酰胺及其含氮代谢物浓度的改变。实验1在长期使用仪器的羔羊胎儿对急性酒精或酸血症操作的反应中验证了这一假设，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，我们假设妊娠晚期的产前酒精暴露相当于人类大脑发育，通过引起酸血症、胎儿谷氨酰胺减少和氧化应激增加而起作用。实验2a将确定酒精或酸血症是否会改变母胎间室和胎儿大脑中谷氨酰胺及其代谢物的浓度及其流动，以及母体谷氨酰胺是否会阻止这些变化。实验2b将测试酒精介导的整个妊娠晚期pH值和谷氨酰胺的降低是否相当于人类大脑发育导致氧化应激增加，以及母体谷氨酰胺是否具有预防作用。具体目的3假设，母亲谷氨酰胺的施用将防止胎儿脑损伤，以应对孕晚期等效酒精暴露（实验3验证了这一假设）。因为已知酒精通过不止一种机制起作用，我们预测谷氨酰胺将基本上但不是完全预防脑损伤，这些发现将使我们处于一个很好的位置，以开发一种实用的，组合的，营养预防，NIAAA战略计划的既定目标。公共卫生相关性：教育未能显著降低胎儿酒精综合征的发生率，这使得了解产前酒精暴露导致神经发育损害的机制，以制定预防和改善策略变得非常重要。在这个提议中，我们测试了几个假设，这些假设可以解释酒精是如何造成这种损害的，并将测试基于这些假设的营养预防。这项研究解决了国家酒精中毒和酒精滥用研究所战略计划中的一个既定目标。

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.