OVINE MODEL SYSTEM FOR ALCOHOL RELATED BIRTH DEFECTS

描述(改编自申请人的摘要)： 这项建议是使用羊(羊)模型系统来解决Fas 与NIAAA的另一个特别感兴趣的领域有关的问题， 适量饮酒。具体目标1将检验母体 妊娠晚期酒精暴露水平太低，不能 产生胎儿缺氧会产生实质性的脑损伤。第二，我们 将确定高剂量的酒精是否会导致缺氧 脑损伤的不成比例的增加。我们将重点关注 小脑、穹窿体部面积测量及立体定位 小脑、大脑皮层、海马结构的逻辑细胞计数， 蓝斑和三叉神经的主要感觉核， 包括已知的表现出差异性的神经元群体的结构 对胎儿酒精暴露和缺氧都很敏感。数据也将 收集与第二个流行的假设有关，即母亲大量饮酒 饮酒会使前列腺素水平发生变化，从而调节酒精 相关的出生缺陷。待评估的其他因变量 包括循环中前列腺素和激素水平、血液动力学 测量、血气、粗大的躯体异常和产前生长测量。 特定目标2将确定长期产前饮酒的影响 暴露(所有三个月)对大脑发育的影响。这款车的设计 实验是由报告的中度和重度饮酒模式驱动的 怀孕期间饮酒的人。具体目标3将检验这一假设 脑损伤在质量上和数量上都会有所不同 比较整个孕期酒精暴露与仅限于 怀孕第三个月。这项提案中提出的问题尚未得到解决 回答的部分原因是缺乏合适的动物模型系统。这个 绵羊模型系统具有几个明显的优势，将在 建议进行的研究。它们包括：1)大脑发育的各个阶段 与人类整个怀孕过程中发生的情况类似的情况也会发生 完全在羊产前；2)一个大的母体/胎儿单位，对 慢性留置导管；以及3)长时间妊娠使其更容易 评估酒精的临界期、阈值剂量和模式 曝光。开发绵羊模型系统最引人注目的原因 这些优势对评估机制特别有价值 造成的损害。总之，这些研究将提供新的、重要的相关数据 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完全一致。

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.