Ovine model system for alcohol related birth defects

酒精相关出生缺陷的绵羊模型系统

• 批准号: 7669345
• 负责人: TIMOTHY A CUDD
• 金额: $ 32.96万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669345
• 关键词: Accounting; Acidosis; Acute; Address; Alcohol-related birth defects; Alcohols; Amino Acids; Apoptosis; Award; Biological Models; Blood flow; Brain; Brain Injuries; Brain Stem; Brain region; Catheters; Cell Count; Cells; Cerebellum; Cessation of life; Control Groups; Data; Development; Education; Elements; Enzymes; Exposure to; Failure; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Fetus; Figs - dietary; Future; Glutamate-Ammonia Ligase; Glutamates; Glutaminase; Glutamine; Glutathione; Glutathione Disulfide; Goals; Hippocampus (Brain); Hour; Human; Incidence; Infusion procedures; Injury; Intervention; Kidney; Liver; Malondialdehyde; Manuscripts; Measurement; Measures; Mediating; Metabolism; Modeling; Mothers; Muscle; National Institute on Alcohol Abuse and Alcoholism; Neurodevelopmental Disorder; Neurons; Nutrient; Nutritional; Nutritionist; Occipital lobe; Oxidative Stress; Parietal Lobe; Pathway interactions; Pattern; Placenta; Plasma; Play; Positioning Attribute; Pregnancy; Preparation; Prevention; Publishing; Purkinje Cells; Reporting; Research; Role; Saline; Sampling; Sheep; Source; Strategic Planning; Supplementation; System; Techniques; Temporal Lobe; Testing; Third Pregnancy Trimester; Tissues; Uterus; Woman; abstracting; alcohol exposure; alcohol prevention; alcohol response; base; brain tissue; cell type; design; drinking; effective intervention; falls; feeding; fetal; frontal lobe; indexing; instrument; neuron loss; novel; olfactory bulb; prevent; public health relevance; research study; response; successful intervention

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.

描述（由申请人提供）：尽管努力教育妇女在怀孕期间不喝酒，但胎儿酒精谱系疾病的发生率并没有下降，因此重要的是要了解产前酒精暴露会导致神经发育损害的机制，以开发预防性和改善策略。在此提案中，我们将利用良好的绵羊模型的独特优势来研究酒精会导致脑损伤并开始探索保护策略的基本机制。我们报告说，酒精会导致母体和胎儿酸血症以及孕妇谷氨酰胺和谷氨酰胺相关代谢产物的减少。我们假设酒精介导的酸血症会降低胎儿谷氨酰胺和与谷氨酰胺相关的代谢产物，这会导致或导致氧化应激和脑损伤的升高。在特定目标1中，我们假设酒精会诱导母体和胎儿酸中毒，从而导致胎儿中谷氨酰胺及其氮代谢物的浓度改变。实验1对急性酒精或酸血症操作的慢性仪器胎儿进行了检验，并将确定母体谷氨酰胺是否会防止代谢产物浓度的变化。在特定的目标2中，我们假设在整个三个月中，相当于人脑发育的产前酒精暴露通过引起酸血症，胎儿谷氨酰胺的减少以及氧化应激的增加来起作用。实验2a将确定酒精或酸血症是否会在母体和胎儿室之间以及胎儿大脑以及孕妇谷氨酰胺的给药中改变谷氨酰胺及其代谢物的浓度及其代谢产物。实验2b将测试酒精介导的pH和谷氨酰胺在第三个三个月中是否减少了人脑发育的同等，导致氧化应激的增加，以及孕妇谷氨酰胺是否是预防性的。特定目标3假设孕产妇谷氨酰胺的给药将防止胎儿脑损伤，以响应第三个三个月的同等酒精暴露（实验3测试了这一假设）。由于酒精是通过多种机制作用的，因此我们预测谷氨酰胺将大大但并不能完全预防脑损伤，并且这些发现将使我们处于良好的位置，以开发实用，组合性，营养预防。公共卫生相关性：教育未能显着降低胎儿酒精综合症的发生率，因此重要的是要了解产前酒精暴露会导致神经发育损害以制定预防和改善策略的机制。在此提案中，我们检验了一些假设，这些假设可以解释酒精如何造成这种损害，并将基于这些假设测试营养预防。这项研究探讨了美国国家酒精中毒和酗酒战略计划中的一个既定目标。