Craniofacial and CNS Pathology in a Mouse FASD Model

描述（由申请人提供）：拟议的基础研究的目的是对产前酒精（乙醇）暴露引起的涉及大脑和面部的病理进行临床相关的发现。这一建议自然建立在我们迄今为止cifasd支持的基础研究的基础上，并继续解决更全面了解母亲饮酒引起的异常的频谱和暴露阶段依赖性的需要。利用完善的FASD小鼠模型，结合创新的技术和方法，并针对3个具体目标，我们建议测试酒精诱导小鼠大脑和面部结构异常的总体假设，这与人类FASD的结构异常一致并提供信息。Aim 1研究补充并扩展了dr。福特和哈蒙德。他们使用磁共振成像（MRI）和密集表面建模（DSM）进行实验，旨在识别暴露阶段相关的大脑和面部异常。Aim 2研究补充并扩展了Sowell小组基于神经影像学的临床研究，同时跟进了我们小鼠模型中脑皮质厚度改变的初步发现。为此，基于mri的区域脑容量和脑皮质厚度变化评估，以及基于dti的成人纤维束和结构连接变化调查

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.