Translational Studies of FASD Using a Sheep Model-U01

描述（由申请人提供）：本联盟的主要目标是确定胎儿酒精谱系障碍（FASD）表型变异的来源（面部畸形、结构性脑损伤和神经行为功能缺陷），促进对结构-功能关系的理解，提高FASD的诊断和早期识别，并制定早期干预措施，以限制高危妊娠的不良后果。动物模型对实现这些目标至关重要。本项目提出了一种新颖的绵羊模型，特别适合FASD的实验转化研究。绵羊在子宫内的大脑发育与人类的大脑发育相对吻合，绵羊产前酗酒产生的大脑和行为影响与FASD一致。这个项目有两个长期目标。第一种方法是使用绵羊模型来比较与人类妊娠早期（1 - 3个月模式）相比，在大脑发育期间，类似的酗酒暴露对大脑发育的影响，与人类妊娠三个月（3- 3个月模型）的大脑发育阶段相似。这些研究评估了用于诊断胎儿酒精综合征（生长、面部畸形、大脑和行为发育）的表型指标，使用的方法明确源自并直接与联盟中人类成分应用的方法合作。这些研究验证了一个普遍的假设，即孕期前三个月后持续的暴饮暴食会对大脑和神经行为发育产生更广泛的影响。目的1将使用结构磁共振成像评估生长、面部形态测量以及对体内脑区域体积的影响。目的2将评估使用眨眼经典条件反射和空间工作记忆的神经行为结果。目的3将通过小脑、海马形成和脑干血清素系统中的神经元计数来评估神经解剖学效应。这些研究旨在与四个人类项目（面部成像（Foroud），脑成像（Sowell），神经行为项目（Mattson）和风险因素/营养项目（Chambers））以及两个小鼠基础科学项目（Zhou; Sulik）相互关联并相互提供信息。第二个目标（目的4）是验证在妊娠期开始补充胆碱会减轻3个月妊娠羊模型中酒精暴露的不良影响的假设。本研究与大鼠胆碱补充项目[基于大鼠的基础科学发展项目（Thomas）]和人类胆碱补充项目[Chambers/Keen的风险因素/营养项目]有明确和互补的合作。这种绵羊模型提供了一个独特的机会，可以比过去更紧密地连接财团的基础和临床部门。

DESCRIPTION (provided by applicant): The main goals of this consortium are to identify sources of variation in fetal alcohol spectrum disorder (FASD) phenotypes (facial dysmorphology, structural brain damage and neurobehavioral functional deficits), to advance understanding of structure-function relationships, to improve diagnosis and early identification of FASD, and to develop early interventions that may limit adverse outcomes in at-risk pregnancies. Animal models are essential to those goals. This project proposes a novel sheep model that is especially well suited for experimental translational studies of FASD. In utero brain development in sheep matches human brain development relatively well, and prenatal binge alcohol exposure in sheep produces brain and behavioral effects consistent with FASD. There are two long-term objectives for this project. The first is to use the sheep model to compare the effects of binge-like alcohol exposure during the period of brain development comparable to that of the human first trimester (1st-trimester mode/) with similar binge-like exposure that extends over the stages of brain development encompassing all three human trimesters (3-trimester model). These studies evaluate phenotypic measures used in the diagnosis of fetal alcohol syndrome-growth, facial dysmorphology, and brain and behavioral development-using methods derived explicitly from and collaboratively linked directly to approaches applied in the human components of the consortium. These studies test the general hypothesis that more pervasive effects on brain and neurobehavioral development will result from binge exposure that continues after the first trimester. Aim 1 will evaluate growth, facial morphometry, and effects on in vivo brain regional volumes using structural magnetic resonance imaging. Aim 2 will assess neurobehavioral outcomes using eyeblink classical conditioning and spatial working memory. Aim 3 will assess neuroanatomical effects via neuronal counts in the cerebellum, hippocampal formation, and brainstem serotonin system. These studies are designed to inter-relate with and reciprocally inform four of the human projects [Facial Imaging (Foroud), Brain Imaging (Sowell), Neurobehavioral project (Mattson), and the Risk Factors/Nutrition project (Chambers)] and the two mouse basic science projects (Zhou; Sulik). The second objective (Aim 4) is to test the hypothesis that choline supplementation initiated periconceptually will attenuate the adverse effects of alcohol exposure in the 3-trimester sheep model. This study was designed with explicit and complementary collaboration with the choline-supplementation projects in rats [the basic science developmental project using rats (Thomas)] and in humans [Risk Factor/Nutrition project of Chambers/Keen]. This sheep model provides a unique opportunity to bridge the basic and clinical arms of the consortium more closely than has been achieved in the past.