Translational Studies of FASD Using a Sheep Model-U01

使用绵羊模型进行 FASD 的转化研究-U01

基本信息

批准号：
7503981
负责人：
TIMOTHY A CUDD
金额：
$ 26.08万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7503981
关键词：
3-Dimensional Address Adolescent Adverse effects Affect Africa Age Age-Months Alcohol consumption Alcohol-Related Neurodevelopmental Disorder Alcohols Animal Model Animals Attenuated Basic Science Behavioral Binding Sites Biology Birth Blinking Brain Brain Injuries Brain Stem Brain imaging Brain region Cells Cerebellar Nuclei Cerebellum Characteristics Child Choline Clinical Clinical Research Collaborations Complement Condition Count Data Depth Development Diagnosis Diagnostic Dietary Intervention Dose Drug Design Dysmorphology Early Diagnosis Early Intervention Early identification Elements Emotional Ethanol Ethnic group Experimental Animal Model Face Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fetal Alcohol Syndrome First Pregnancy Trimester Frequencies Future Genetic Polymorphism Goals Growth Hippocampal Formation Hippocampus (Brain)Human Image Image Analysis Individual Infant Infant Development Informal Social Control Informatics Intervention Knowledge Language Language Development Learning Life Link Los Angeles Machine Learning Magnetic Resonance Magnetic Resonance Imaging Measures Memory Methods Microcephaly Mission Modeling Morphology Moscow Mothers Mus Neonatal Neural Cell Adhesion Molecule L1 Neurobiology Neurons New Mexico Numbers Outcome Partner in relationship Pattern Performance Phenotype Pilot Projects Play Population Pregnancy Principal Investigator Rattus Recording of previous events Request for Applications Research Research Design Research Personnel Research Project Grants Resolution Risk Risk Factors Rodent Rodent Model Role Schools Sensitivity and Specificity Serotonin Severities Sheep Short-Term Memory Signal Pathway Signal Transduction Site Source Specificity Staging Structure Structure-Activity Relationship Sum Supplementation System Technology Testing Therapeutic Three-Dimensional Image Three-Dimensional Imaging Time Toddler Ukraine Ultrasonography Upper arm Variant Woman Work alcohol exposure alcohol sensitivity analog base binge drinking brain behavior brain morphology brain volume classical conditioning cognitive control conditioning critical developmental period data integration dentate gyrus design drinking fetal diagnosis follow-up granule cell hippocampal pyramidal neuron improved in utero in vivo infancy literacy morphometry mouse model multidisciplinary neurobehavioral neurobehavioral test neuron loss northern plains novel nutrition postnatal prenatal prevent programs prospective reconstruction research study social species difference three dimensional structure translational study

项目摘要

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.

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，以增进对结构功能关系的理解，改善 FASD 的诊断和早期识别，并制定早期干预措施，限制高危妊娠的不良后果。动物模型对于实现这些目标至关重要。该项目提出了一种新型绵羊模型，特别适合 FASD 的实验性转化研究。绵羊的子宫内大脑发育与人类大脑发育相对较好，绵羊产前酗酒会产生与胎儿酒精谱系障碍 (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来比较在大脑发育期间与人类妊娠早期（妊娠早期模式/）相比，在大脑发育期间暴饮暴食的影响，以及在各个阶段延伸的类似暴饮暴食的影响。涵盖人类所有三个三个月期的大脑发育（三个月期模型）。这些研究评估了用于诊断胎儿酒精综合症的表型测量——生长、面部畸形、大脑和行为发育——使用的方法明确源自并直接与应用于该联盟的人类成分的方法相关联。这些研究检验了一个普遍的假设，即妊娠早期持续的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评估生长、面部形态测量以及对体内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。目标 3 将通过小脑、海马结构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）、大脑成像（Sowell）、神经行为项目（Mattson）和风险因素/营养项目（Chambers）]以及两个项目相互关联并相互提供信息。小鼠基础科学项目（Zhou；Sulik）。第二个目标（目标 4）是检验以下假设：围孕期开始补充胆碱会减轻妊娠 3 个月绵羊模型中酒精暴露的不利影响。这项研究的设计与大鼠胆碱补充项目[使用大鼠的基础科学发展项目（托马斯）]和人类[钱伯斯/基恩的风险因素/营养项目]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来连接基础和临床该财团的武器比过去更加紧密。