Mechanisms and Nutritional Intervention for Fetal Alcohol Spectrum Disorders

胎儿酒精谱系障碍的机制和营养干预

• 批准号: 8049220
• 负责人: Shannon E. Washburn
• 金额: $ 8.67万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-20 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049220
• 关键词: Acidosis; Acids; Acute; Address; Alcohol Nutrition; Alcohol consumption; Alcohols; Amino Acids; Apoptosis; Area; Brain; Brain Injuries; Brain region; Cell Count; Cells; Chronic; Complement; Data; Development; Dietary Intervention; Doctor of Philosophy; Education; Evaluation; Experimental Designs; Failure; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Fetal Growth; Fetus; Foundations; Funding; Future; Glutamine; Glutathione; Goals; Homeostasis; Human; Incidence; Injury; Intervention; Intervention Studies; Investigation; Lead; Learning; Left; Mediating; Medical Research; Mentors; Meta-Analysis; Metabolism; Modeling; Mothers; National Institute on Alcohol Abuse and Alcoholism; Neurodevelopmental Disorder; Neurons; Nutritional; Nutritional Study; Oxidative Stress; Pathway interactions; Plasma; Positioning Attribute; Prevention; Process; Reactive Oxygen Species; Research; Research Personnel; Resources; Sampling; Science; Sheep; Strategic Planning; Stream; Supplementation; Testing; Training; alcohol effect; alcohol exposure; alcohol research; alcohol response; base; body system; career; drinking; effective intervention; experience; falls; fetal; fetal programming; field study; in utero; indexing; neuron loss; prevent; public health relevance; regional difference; research study; response

DESCRIPTION (provided by applicant): 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. 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. 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.

描述（由申请人提供）：产前酒精暴露会通过多种力学途径造成神经发育损伤，这些途径仍然鲜为人知。只有通过鉴定这些机制，才有可能制定预防和改善策略。假设孕产妇/胎儿pH，氧化应激和氨基酸代谢改变的改变对于造成神经发育损害在机械上很重要。通过孕产妇给药谷氨酰胺（在受酒精破坏的几个过程中，谷氨酰胺）的校正可以提供饮酒诱导的神经发育损害。因此，谷氨酰胺可能被证明是对酒精介导的神经发育疾病的成功且合理的营养干预策略，从而实现了当前的NIAAA战略倡议。这些实验将利用现在已建立的绵羊模型的独特优势，在整个人类胎儿脑发育中，feto-Mathnal单位完好无损。绵羊模型允许同时进行胎儿和母体采样，这是对拟议机制和营养干预策略进行研究的必要性。该提案的第一个具体目的是评估酒精引起的胎儿谷氨酰胺，与谷氨酰胺相关的代谢产物和其他氨基酸的变化，以应对急性和慢性酒精暴露范式。急性暴露初步数据显示，胎儿谷氨酰胺以及多种其他氨基酸的显着降低，这对胎儿生长，酸碱稳态，抗氧化应激（脑损伤）和胎儿编程具有严重影响。这些减少及其后果可能是酒精引起的神经发育损害的主要机制。第二个特定目的是量化胎儿大脑中氧化应激的指标。初步数据表明，响应产前酒精暴露的大脑区域之间氧化应激的区域差异。这种选择性与绵羊模型中慢性酒精暴露时观察到的神经元丧失相关。酒精介导的谷氨酰胺降低可能会通过损害氧化应激的防御损害，因为谷氨酰胺是谷胱甘肽的前体。第三个具体目的是测试补充谷氨酰胺的保护能力，以防止特定目标1和2中的变化，并记录任何免受酒精诱导神经元损失的保护。它还将提供数据来表征慢性酒精与急性酒精暴露发生的变化，以及是否发生任何补偿性变化。威尔逊博士离开了私人兽医实践，进入了医学研究领域，并满足了生物医学科学博士学位的大约75％的要求。她的长期职业目标是成为酒精研究领域的独立调查员。她成立了一个由五位导师组成的委员会，以最大程度地发挥自己的学习潜力，并在接近涉及许多不同的器官系统和研究专业领域的研究领域中获得优势。该提案将导致的培训，资源，协作关系和数据池将使她能够开发新的想法和项目以及资金流以支持它们。营养和酒精研究中的培训和经验以及她的兽医专业知识和背景将使她唯一地使她朝着与她的指导团队根本不同的方向分裂，并在未来发展了高度独立和富有成效的研究职业。 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。该提案测试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。这项研究旨在解决NIAAA战略计划中的既定目标。