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（改编自申请人的摘要）：总体目的 该提案是使用绵羊（绵羊）模型系统来解决 FAS 与 NIAAA 另一个特别感兴趣的领域相关的问题， 适量饮酒。 具体目标 1 将检验以下假设：母亲 妊娠晚期的酒精暴露水平太低，无法 胎儿缺氧的产生会产生大量的脑损伤。 第二，我们 将确定介导缺氧的高剂量酒精是否会导致 脑损伤的增加不成比例。 我们将重点关注 小脑畸形、胼胝体面积测量和立体测量 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 收集的数据与第二个流行的假设有关，即大量的产妇酒精 消费会改变介导酒精的前列腺素水平 相关出生缺陷。 需要评估的其他因变量 包括前列腺素和激素的循环水平、血流动力学 测量、血气、严重躯体异常和产前生长测量。 具体目标 2 将确定长期产前饮酒的影响 暴露（所有三个月期）对大脑发育的影响。 为此设计 实验是由中度和重度饮酒模式驱动的 怀孕期间饮酒者。 具体目标 3 将检验以下假设： 脑损伤在质量和数量上都会有所不同 比较整个妊娠期间的酒精暴露与限制的暴露 第三个三个月。 该提案中提出的问题尚未得到解决 部分原因是缺乏合适的动物模型系统。 这 绵羊模型系统有几个明显的优势，将在 拟议的研究。 其中包括：1）大脑发育的阶段 与人类妊娠期间发生的情况类似的情况也会发生 完全在绵羊产前进行； 2) 较大的母体/胎儿单位能够耐受 长期留置插管； 3）较长的妊娠期使其更容易 评估关键时期、阈剂量和酒精模式 接触。 开发绵羊模型系统最令人信服的理由 这些优点对于评估机制特别有价值 的损坏。 总之，这些研究将提供相关的新的重要数据 胎儿酒精暴露和脑损伤尚未得到解决 与其他动物模型系统充分结合。