Translational Studies of FASD Using a Sheep Model-U01

描述(由申请人提供)：该联盟的主要目标是确定胎儿酒精谱系障碍(FASD)表型(面部畸形、结构性脑损伤和神经行为功能缺陷)的变异来源，增进对结构-功能关系的了解，改进FASD的诊断和早期识别，并开发可能限制高危妊娠不良后果的早期干预措施。动物模型对于实现这些目标至关重要。本项目提出了一种新的绵羊模型，该模型特别适合于FASD的实验翻译研究。绵羊在子宫内的大脑发育与人类大脑发育相对较好，而绵羊出生前酗酒会产生与FASD一致的大脑和行为影响。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大脑发育期间酗酒的影响，与人类早期三个月(第一个三个月的妊娠模式)相似的类似的暴饮式酒精暴露的影响，包括包括所有三个人类三个月的大脑发育阶段(三个三个月的模型)。这些研究评估了用于诊断胎儿酒精综合征的表型指标-生长、面部畸形以及大脑和行为发育-使用的方法明确地源自该联盟的人类组成部分，并与其直接协作联系。这些研究测试了普遍的假设，即在怀孕前三个月后继续暴饮暴食将对大脑和神经行为发育产生更普遍的影响。目标1将使用结构磁共振成像来评估生长、面部形态测量以及对活体大脑区域体积的影响。目标2将使用眨眼、经典条件反射和空间工作记忆来评估神经行为结果。目的3将通过小脑、海马结构和脑干5-羟色胺系统中的神经元计数来评估神经解剖学效应。这些研究旨在与人类的四个项目[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)]和两个小鼠基础科学项目(周；Sulik)相互联系并相互提供信息。第二个目标(目标4)是在妊娠3个月的绵羊模型中验证这样的假设，即在妊娠3个月的绵羊模型中，从概念上开始补充胆碱将减轻酒精暴露的不良影响。这项研究是与胆碱补充项目[使用大鼠的基础科学发展项目(Thomas)]和人类[钱伯斯/基恩的风险因素/营养项目]进行明确和互补的合作设计的。这种绵羊模型提供了一个独特的机会，架起了基础和临床之间的桥梁 与过去相比，财团之间的关系更加紧密。

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.