Craniofacial and CNS Pathology in a Mouse FASD Model

小鼠 FASD 模型中的颅面和中枢神经系统病理学

• 批准号: 8400958
• 负责人: SHONAGH K O'LEARY-MOORE
• 金额: $ 31.32万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-10 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8400958
• 关键词: Acute; Address; Adolescent; Adult; Affect; Alcohol consumption; Alcohols; Area; Atlases; Basic Science; Biological; Brain; Brain region; Cajal-Retzius cells; Cells; Cerebrum; Clinical; Clinical Research; Complement; Congenital Abnormality; Defect; Dependence; Dependency; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease model; Dysmorphology; Exhibits; Face; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fiber; First Pregnancy Trimester; Funding; Goals; Histopathology; Human; Image; Image Analysis; Immunohistochemistry; Individual; Investigation; Knowledge; Magnetic Resonance Imaging; Methods; Modeling; Mus; Outcome; Pathology; Pattern; Period Analysis; Population; Prosencephalon; Public Health; Research; Research Personnel; Resolution; Services; Specimen; Staging; Surface; Techniques; Testing; Thick; Time; Treatment Protocols; Work; alcohol exposure; base; brain volume; clinically relevant; clinically significant; craniofacial; critical period; density; design; fetal; human data; innovative technologies; insight; interest; mature animal; mouse model; neuroimaging; novel; postnatal; prenatal; research study

DESCRIPTION (provided by applicant): The objective of the proposed basic research is to make clinically-relevant discoveries regarding prenatal alcohol (ethanol) exposure-induced pathology involving the brain and face. This proposal builds naturally on our CIFASD-supported basic research to date and continues to address the need for a more complete understanding of the spectrum and exposure stage-dependency of abnormalities caused by maternal alcohol use. Utilizing a well-established FASD mouse model, along with innovative technologies and approaches, and addressing 3 Specific Aims, we propose to test the overall hypothesis that alcohol induces structural abnormalities of the brain and face in mice that are consistent with and informative for those in human FASD. The Aim 1 studies compliment and extend the clinical research proposed by Drs. Foroud and Hammond. They employ Magnetic Resonance Imaging (MRI) and dense surface modeling (DSM) for experiments that are designed to identify exposure stage-dependent correlative abnormalities of the brain and face. The Aim 2 studies compliment and extend the Sowell group's neuroimaging-based clinical studies while following up on preliminary findings of cerebro-cortical thickness alterations in our mouse model. For this, MRI-based assessments of regional brain volumes and cerebro-cortical thickness changes, along with DTI-based investigations of fiber tract and structural connectivity alterations in adult animals are proposed. The Aim 3 studies are directed toward further defining the histopathology and genesis of early prenatal alcohol exposure- induced regional brain dysmorphology. They will employ routine histological methods, as well as immunohistochemistry, and stereology. Specimens selected for detailed histological analyses will include those postnatal brains that had previously been imaged and analyzed for Aim 2. Additional Aim 3 studies will focus on prenatal stages and will address the novel concept that early alcohol insult yields changes in Cajal-Retzius cell populations; changes that underlie subsequent cerebro-cortical lamination defects. The proposed work is consistent with the overall purpose/goals of the CIFASD in that it will facilitate diagnosis of the full range of birth defects associated with prenatal alcohol exposure, and it will aid in elucidating biological mechanisms that contribute to alcohol teratogenesis. The results of the proposed studies promise to fill a significant FASD research void, inform human clinical research, and continue to highlight the first trimester as a critical period for alcohol-induced defects of the face and brain. PUBLIC HEALTH RELEVANCE: Fetal Alcohol Spectrum Disorder (FASD) remains a major public health problem. The proposed research employs a well-established mouse model to answer FASD-related questions that are impossible to address in clinical studies. Focusing on stage of exposure-dependent facial and brain abnormalities, the results of this work promise to expand our understanding of the temporal dependence, interrelatedness, and mechanisms underlying birth defects that result from maternal alcohol use.

描述（由申请人提供）：拟议的基础研究的目的是使有关临床上的酒精（乙醇）暴露于涉及大脑和面部的病理。该建议自然建立在我们迄今为止的CIFASD支持的基础研究上，并继续满足对孕产妇使用饮酒引起的异常的频谱和暴露阶段依赖性的需求。利用良好的FASD小鼠模型，以及创新的技术和方法，并解决了3个特定目标，我们建议测试总体假设，即酒精会诱导小鼠的结构异常，这与人类FASD中的人一致并提供了信息。目标1研究补充并扩展了DRS提出的临床研究。 Foroud和Hammond。他们采用磁共振成像（MRI）和致密的表面建模（DSM）进行实验，这些实验旨在识别大脑和面部的暴露阶段依赖性相关异常。 AIM 2研究补充并扩展了Sowell组基于神经成像的临床研究，同时跟踪了小鼠模型中脑皮层厚度改变的初步发现。为此，基于MRI的区域脑体积和脑皮质厚度的评估以及基于DTI的纤维道和成人结构连通性改变的研究 提出了动物。 AIM 3研究是针对进一步定义产前酒精早期诱导的区域脑畸形学的组织病理学和起源。他们将采用常规的组织学方法以及免疫组织化学和立体学。选择用于详细组织学分析的标本将包括那些先前对AIM 2进行成像和分析的产后大脑。其他目标3研究将重点放在产前阶段上，并将解决新的概念，即早期酒精侮辱会导致Cajal-Retzius细胞群体的变化；随后的脑皮质层压缺陷是基础的变化。拟议的工作与CIFASD的总体目的/目标一致，因为它将促进与产前酒精暴露相关的全部出生缺陷的诊断，并且它将有助于阐明有助于酒精致死的生物学机制。拟议研究的结果有望填补大量的FASD研究无效，为人类的临床研究提供信息，并继续强调头三个月，作为酒精引起的面部和大脑缺陷的关键时期。 公共卫生相关性：胎儿酒精谱系障碍（FASD）仍然是一个主要的公共卫生问题。拟议的研究采用公认的小鼠模型来回答与FASD相关的问题，这些问题在临床研究中无法解决。这项工作的重点关注依赖暴露的面部和脑部异常，有望扩大我们对孕产妇使用饮酒产生的先天缺陷的时间依赖性，相互关系和机制的理解。