In-utero characterization of embryonic mouse brain development and injury with MRI

MRI 表征小鼠胚胎脑发育和损伤的子宫内特征

• 批准号: 9164496
• 负责人: Dan Wu
• 金额: $ 21.15万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9164496
• 关键词: Abdomen; Acute; Animal Model; Area; Base of the Brain; Behavioral; Birth; Brain; Brain Injuries; Cerebral Palsy; Clinical; Clinical Research; Cognitive; Development; Diagnostic; Diffusion Magnetic Resonance Imaging; Edema; Elements; Embryo; Embryonic Development; Evaluation; Event; Exhibits; Exposure to; Histology; Histopathology; Human; Image; Imaging Device; Imaging Techniques; Immune; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Intervention; Knowledge; Life; Link; Lipopolysaccharides; Longitudinal Studies; Magnetic Resonance Imaging; Maps; Measurement; Measures; Modality; Modeling; Molecular; Monitor; Mothers; Motion; Mus; Neurologic; Neuronal Injury; Outcome; Pathology; Pattern; Performance; Perinatal; Phenotype; Pregnancy; Premature Birth; Property; Research; Resolution; Risk; Rodent Model; Staging; Structure; T2 weighted imaging; Techniques; Time; Tissues; Translating; Weight; Work; base; brain morphology; contrast imaging; diffusion weighted; fetal; fetal brain injury; human disease; image processing; imaging biomarker; imaging platform; improved; in utero; injured; innovation; interest; mouse model; novel; response to injury; spatiotemporal; tool; treatment response; white matter; white matter damage

Project summary: We propose to establish an integrated imaging platform for in-utero monitoring of the embryonic mouse brain development and injury. We will investigate a mouse model of intrauterine inflammatory injury in this project, which induces well-defined phenotypes of fetal neuronal injury. In-utero MRI will be useful to non-invasively detect the injury and monitor the injury progression, in addition to conventional histological examination. We will develop novel techniques to overcome the challenges for in-utero MRI, such as the fetal and maternal motion. A localized imaging technique will be used to focus the imaging field-of-view on selected mouse embryo instead of the entire abdomen, which leads to accelerated acquisition and reduced exposure to motion, as we previously demonstrated. Fast imaging sequences and motion correction techniques will be integrated to achieve 3D high-resolution MRI to resolve the miniature structures in the embryonic mouse brain. The technique will be extended for simultaneous imaging of multiple embryos to improve the throughput. Based on these innovations, multi-modality MRI including T1- and T2-weighted imaging, diffusion-weighted and diffusion tensor imaging will be achieved collectively to characterize the brain morphology and microstructural organization. We will first perform in-utero examination of the normal embryonic mouse brain development from embryonic day 14 to 18. The brain volumetric changes will be quantified from high-resolution T1/T2 images, and the microstructural changes, such as cortical and white matter development will be characterized with diffusion MRI. Using the multi-contrast in-utero MRI tools, and the baseline information from normal brain development, we will examine a mouse model of inflammatory fetal brain injury, induced by intrauterine injection of lipopolysaccharide. Acute edema will be captured from T2- and diffusion-weighted contrasts; while changes in brain morphology, damages in major white matter and cortical structures will be followed with anatomical images and diffusion MRI metrics. The spatiotemporal patterns of injury progression will be characterized by comparing the time courses of the MRI measurements in the injured and sham groups. We will also investigate two time windows of the injury onset at the middle and late gestation stages in order to understand the impacts of the timing of injury. The underlying pathology of the MRI findings will be examined with an array of immune-histological markers, and the MRI-histopathology correlations will be pursued. If the measurements are successful, we will establish multi- contrast MRI markers of the inflammatory fetal brain injury, and demonstrate their pathological implications. The proposed pioneer work will be one of the first studies to achieve in-utero monitoring of embryonic mouse brain development and injury. The findings would contribute important knowledge to human fetal MRI studies as it may reveal the link between MRI and histology markers. The proposed imaging platform will also be useful to evaluate intervention strategies and monitor treatment responses in small animal models, and the techniques are translatable to clinical scanners for safe examination of human fetal brains.

项目概要： 我们建议建立一个集成的成像平台，用于胚胎小鼠脑的宫内监测 发展和伤害。我们将在这个项目中研究子宫内炎性损伤的小鼠模型， 其诱导明确的胎儿神经元损伤表型。子宫内MRI将有助于非侵入性地 除了常规的组织学检查之外，还检测损伤并监测损伤进展。 我们将开发新的技术来克服子宫内MRI的挑战，例如胎儿和母体的MRI。 议案将使用局部成像技术将成像视野聚焦在选定的小鼠胚胎上 而不是整个腹部，这导致加速采集和减少暴露于运动，因为我们 以前演示过。快速成像序列和运动校正技术将被集成，以实现 3D高分辨率MRI用于解析胚胎小鼠大脑中的微型结构。这项技术将是 扩展用于多个胚胎的同时成像以提高通量。基于这些创新， 多模态MRI包括T1和T2加权成像、扩散加权和扩散张量成像， 共同实现表征大脑形态和微观结构组织。我们将首先 对胚胎14 - 18天的正常胚胎小鼠脑发育进行子宫内检查。 脑体积变化将从高分辨率T1/T2图像中量化，并且微结构变化将从高分辨率T1/T2图像中量化。 变化，如皮质和白色物质的发育将用弥散MRI表征。 使用子宫内多对比MRI工具，以及正常大脑发育的基线信息，我们将 检查通过宫内注射脂多糖诱导的炎性胎脑损伤的小鼠模型。 急性水肿将从T2加权和弥散加权对比中捕获;而脑形态学的变化， 主要白色物质和皮质结构的损伤将通过解剖图像和弥散MRI进行随访 指标.损伤进展的时空模式将通过比较时间进程来表征 的MRI测量值。我们还将调查受伤的两个时间窗口 在妊娠中期和晚期发病，以了解损伤时间的影响。的 将用一系列免疫组织学标记物检查MRI结果的潜在病理学， 将追踪MRI-组织病理学相关性。如果测量成功，我们将建立多个- 对比炎性胎脑损伤的MRI标志物，并说明其病理意义。 拟议的先驱工作将是实现胚胎小鼠子宫内监测的首批研究之一 大脑发育和损伤。这些发现将为人类胎儿MRI研究提供重要知识， 它可能揭示MRI和组织学标志物之间的联系。拟议的成像平台也将有助于 在小动物模型中评估干预策略并监测治疗反应， 可用于临床扫描仪，以安全检查人类胎儿大脑。