Craniofacial and CNS Pathology in a Mouse FASD Model

描述（由申请人提供）：拟议基础研究的目的是对产前酒精（乙醇）摄入诱导的涉及大脑和面部的病理学进行临床相关发现。该提案自然建立在我们迄今为止由CIFASD支持的基础研究基础上，并继续解决更全面了解母体饮酒引起的异常的频谱和暴露阶段依赖性的需求。利用完善的FASD小鼠模型，沿着创新的技术和方法，并解决3个特定的目标，我们建议测试的整体假设，酒精诱导大脑和面部的结构异常的小鼠是一致的，并为那些在人类FASD的信息。目标1研究补充并扩展了Foroud和哈蒙德博士提出的临床研究。他们采用磁共振成像（MRI）和密集表面建模（DSM）的实验，旨在确定暴露阶段依赖的相关异常的大脑和面部。Aim 2研究补充并扩展了Sowell小组基于神经成像的临床研究，同时跟踪了我们小鼠模型中大脑皮层厚度改变的初步发现。为此，基于MRI的局部脑体积和皮层厚度变化的评估，沿着基于DTI的纤维束和结构连接改变的调查， 动物被提议。目的3研究旨在进一步确定早期产前酒精暴露诱导的局部脑畸形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体视学。选择用于详细组织学分析的样本将包括先前已针对目标2进行成像和分析的出生后大脑。额外的目标3研究将集中在产前阶段，并将解决新的概念，即早期酒精损伤产生的Cajal-Retzius细胞群的变化;变化的基础，随后的皮质层缺陷。拟议的工作与CIFASD的总体目的/目标一致，因为它将有助于诊断与产前酒精暴露相关的各种出生缺陷，并有助于阐明酒精致畸的生物学机制。拟议研究的结果有望填补一个重要的FASD研究空白，为人类临床研究提供信息，并继续强调妊娠早期是酒精引起的面部和大脑缺陷的关键时期。

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.