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）：拟议基础研究的目的是就产前酒精（乙醇）暴露引起的涉及大脑和面部的病理学做出临床相关的发现。该提案自然地建立在我们迄今为止 CIFASD 支持的基础研究的基础上，并继续满足更全面地了解孕产妇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 小鼠模型以及创新技术和方法，并解决 3 个具体目标，我们建议测试酒精会导致小鼠大脑和面部结构异常的总体假设，该假设与人类胎儿酒精谱系障碍（FASD）。 Aim 1 研究补充并扩展了 Drs. 提出的临床研究。福鲁德和哈蒙德。他们采用磁共振成像（MRI）和致密表面建模（DSM）进行实验，旨在识别大脑和面部与暴露阶段相关的相关异常。 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，同时对我们的小鼠模型中大脑皮质厚度变化的初步发现进行了跟踪。为此，基于 MRI 的区域脑容量和大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的研究 提议动物。 Aim 3 研究旨在进一步明确早期产前酒精暴露引起的区域脑形态异常的组织病理学和起源。他们将采用常规组织学方法以及免疫组织化学和体视学。选择进行详细组织学分析的样本将包括之前为目标 2 进行成像和分析的出生后大脑。其他目标 3 研究将集中于产前阶段，并将解决早期酒精损伤会导致 Cajal-Retzius 细胞群发生变化的新概念；导致随后的大脑皮质层状缺陷的变化。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各种出生缺陷的诊断，并将有助于阐明导致酒精致畸的生物学机制。拟议研究的结果有望填补 FASD 研究的重大空白，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。 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。拟议的研究采用成熟的小鼠模型来回答临床研究中无法解决的 FASD 相关问题。这项工作的结果重点关注暴露依赖性面部和大脑异常的阶段，有望扩大我们对母亲饮酒导致出生缺陷的时间依赖性、相互关联性和潜在机制的理解。