Translational Studies of FASD Using a Sheep Model-U01

使用绵羊模型进行 FASD 的转化研究-U01

• 批准号: 7343058
• 负责人: TIMOTHY A CUDD
• 金额: $ 26.71万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 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/7343058
• 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

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.

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.动物模型对于这些目标至关重要。该项目提出了一种新型的绵羊模型，特别适合FASD的实验翻译研究。在子宫内发育中，绵羊的大脑发育与人脑发育相对匹配，并且绵羊的产前暴饮暴食会产生与FASD一致的大脑和行为效应。该项目有两个长期目标。首先是使用绵羊模型比较大脑发育期间暴饮暴食的影响，可与人类孕早期（第1个孕地模式/）相当的大脑发育时期与类似的暴饮暴食暴露相当，该暴露范围延伸到脑发育阶段，该阶段遍布大脑发育阶段，包括所有三个人类三膜（3-孕期）。这些研究评估了用于诊断胎儿酒精综合征增长，面部畸形学以及大脑和行为发展的方法的表型措施，这些方法明确地得出，并直接与在人类联盟人类组成部分中应用的方法直接链接。这些研究检验了一般假设，即对大脑和神经行为的发育更加普遍影响将是由于孕期后持续的暴饮暴食而引起的。 AIM 1将使用结构磁共振成像评估生长，面部形态计算和对体内大脑区域体积的影响。 AIM 2将使用EykeBlink经典调节和空间工作记忆来评估神经行为结果。 AIM 3将通过小脑，海马形成和脑干5-羟色胺系统的神经元计数评估神经解剖学效应。这些研究的设计旨在与四个人类项目（Foroud），脑成像（Sowell），Neurobehavioral Project（Mattson）以及风险因素/营养项目（Chambers）（Chambers）（Chambers）]和两个小鼠基本科学项目（Zhou; Sulik）。第二个目标（AIM 4）是检验以下假设：补充胆碱的胆碱在3孕期中会减轻酒精暴露的不利影响。这项研究是通过与大鼠（使用大鼠基础科学发展项目（Thomas）的基础科学发展项目）和人类[Chambers/Heen的危险因素/营养项目]的大鼠（基础科学发展项目）的明确和互补合作设计的。这种绵羊模型提供了一个独特的机会来弥合基本和临床 财团的武器比过去更接近。