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，以促进对结构-功能关系的理解，改善FASD的诊断和早期识别，并开发可能限制高危妊娠不良结局的早期干预措施。动物模型对这些目标至关重要。该项目提出了一种新的绵羊模型，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匹配，而绵羊产前酗酒会产生与FASD一致的大脑和行为影响。该项目有两个长期目标。第一个是使用绵羊模型比较大脑发育期间类似于人类前三个月（第一个三个三个月模式/）的酗酒暴露与类似的酗酒暴露的影响，这些饮酒暴露在大脑发育的各个阶段，包括所有三个月（第三个月模型）。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、大脑和行为发育--使用的方法明确地来源于该联盟中人类组成部分的方法，并与之直接合作。这些研究验证了一个普遍的假设，即对大脑和神经行为发育的更普遍的影响将来自于在头三个月后继续的暴饮暴食。目的1将评估生长，面部形态测量，并在体内使用结构磁共振成像脑区域体积的影响。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）]和两个小鼠基础科学项目（Zhou; Sulik）相互关联并提供信息。第二个目的（目的4）是检验这一假设，即胆碱补充开始periconceptually将减弱酒精暴露在3个月的绵羊模型的不利影响。本研究的设计与大鼠[使用大鼠的基础科学发展项目（托马斯）]和人类[Chambers/Keen的风险因素/营养项目]的胆碱补充项目进行了明确和互补的合作。这种绵羊模型提供了一个独特的机会，桥梁的基础和临床 集团的武器比过去更加紧密。

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.