OVINE MODEL SYSTEM FOR ALCOHOL RELATED BIRTH DEFECTS

与酒精相关的先天缺陷的绵羊模型系统

• 批准号: 2894124
• 负责人: TIMOTHY A CUDD
• 金额: $ 22.52万
• 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 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2894124
• 关键词: cephalometry; chronic brain damage; congenital disorders; developmental neurobiology; disease /disorder model; dosage; eicosanoid metabolism; embryo /fetus toxicology; ethanol; fetal alcohol syndrome; gestational age; hypoxia; micrencephaly; prostaglandins; sheep

DESCRIPTION (Adapted from the APPLICANT'S ABSTRACT): The overall purpose of this proposal is to use an ovine (sheep) model system to address FAS questions in conjunction with another of NIAAA's areas of special interest, moderate drinking. Specific Aim 1 will test the hypothesis that maternal alcohol exposure levels during the third trimester that are too low to produce fetal hypoxia will produce substantial brain damage. Second, we will determine if high doses of alcohol that mediate hypoxia result in disproportionate increases in brain injury. We will focus on microencephaly, area measurements of the corpus callosum and on stereo logical cell counts in the cerebellum, neocortex, hippocampal formation, locus coeruleus and the principal sensory nucleus of the trigeminal nerve, structures that include populations of neurons known to exhibit differential sensitivity to both fetal alcohol exposure and hypoxia. Data also will be gathered related to a second popular hypothesis, that heavy maternal alcohol consumption produces altered prostaglandin levels that mediate alcohol related birth defects. Additional dependent variables to be assessed include circulating levels of prostaglandins and hormones, hemodynamic measures, blood gases, gross somatic anomalies and prenatal growth measures. Specific Aim 2 will determine the effects of long-term prenatal alcohol exposure (all three trimesters) on brain development. The design for this experiment is driven by drinking patters reported in moderate and heavy drinkers during pregnancy. Specific Aim 3 will test the hypothesis that brain damage will be qualitatively as well as quantitatively different when comparing alcohol exposure throughout gestation with exposure restricted to third trimester. The questions raised in this proposal have not yet been answered due in part to the lack of a suitable animal model system. The sheep model system has several distinct advantages that will be exploited in the proposed studies. These include: 1) the stages of brain development comparable to that which occurs throughout gestation in humans also occur entirely prenatally in the sheep; 2) a large maternal/fetal unit tolerant of chronic indwelling cannulae; and 3) a long gestation making it much easier to evaluate critical periods, threshold doses, and patterns of alcohol exposure. The most compelling reason for developing the ovine model system is that these advantages are particularly valuable for evaluating mechanisms of damage. Together, these studies will provide new, important data related to fetal alcohol exposure and brain damage that have not been addressed adequately with other animal model systems.

描述（改编自申请人摘要）： 该建议是使用绵羊模型系统来解决FAS 与NIAAA特别感兴趣的另一个领域相结合的问题， 适度饮酒。 具体目标1将检验以下假设： 在妊娠晚期，酒精暴露水平太低， 产生胎儿缺氧会对大脑造成严重损伤。 二是 将确定是否高剂量的酒精介导缺氧导致 脑损伤的不成比例的增加。 我们将专注于 小脑畸形，胼胝体面积测量和立体 小脑、新皮质、海马结构中的逻辑细胞计数， 蓝斑和三叉神经的主要感觉核， 包括已知表现出差异的神经元群体的结构， 对胎儿酒精暴露和缺氧的敏感性。 数据也将 与第二个流行的假设有关， 饮酒会改变前列腺素水平， 与出生缺陷有关。 待评估的其他因变量 包括循环中的肾上腺素和激素水平、血液动力学 测量、血气分析、大体躯体异常和产前生长测量。 具体目标2将确定长期产前酒精的影响 暴露（所有三个孕期）对大脑发育的影响。 这个的设计 实验是由中度和重度饮酒模式驱动的 怀孕期间饮酒 具体目标3将检验以下假设： 脑损伤将在质和量上有所不同， 将整个妊娠期的酒精暴露与仅限于 妊娠晚期 该提案中提出的问题尚未得到 部分原因是缺乏合适的动物模型系统。 的 绵羊模型系统有几个明显的优势，将被利用， 建议的研究。 这些包括：1）大脑发育的阶段 与人类整个妊娠期发生的类似， 完全产前在羊; 2）一个大的母体/胎儿单位耐受 长期留置套管; 3）妊娠时间长， 评估关键时期，阈值剂量和酒精模式 exposure. 开发绵羊模型系统最令人信服的原因是 这些优点对于评估机制特别有价值， 的损害。 总之，这些研究将提供新的，重要的数据， 胎儿酒精暴露和脑损伤的问题还没有得到解决 与其他动物模型系统相比。