Imaging Neonatal Hypoxic Ischemic Injury

摘要 缺血性缺氧（HI）损伤婴儿的白色物质和灰质， 死亡率和发病率。探讨新生儿HI损伤的病理机制， 治疗方面，新生儿缺氧缺血性损伤的动物模型已经建立并广泛应用。在这 项目，新的在体内磁共振成像的组织微观结构和神经元活动将是 研究新生儿HI损伤的进展和治疗性低温的影响。 小鼠模型 在目标1中，我们将研究新型扩散MRI（dMRI）技术对组织显微结构的敏感性， 由HI损伤引起的变化。初步结果表明，所提出的成像技术可以更多地 比传统的dMRI技术更灵敏地检测轻度脑损伤， 常规dMRI信号的伪归一化。我们将使用组织学和电子显微镜， 确定细胞和亚细胞结构变化的水平， 与dMRI信号，并使用数值模拟来了解它们之间的关系。的 知识将用于优化成像方案，以检测新生儿HI后的关键结构变化。 在目标2中，我们将使用锰增强MRI（MEMRI）检查损伤。先前的研究表明 MEMRI对比反映了大脑中的神经元活动，并可以选择性地增强具有 新生儿HI后的细胞凋亡和炎症。在这个目标中，我们将研究MEMRI的敏感性损失的 新生儿HI后的神经元活性、凋亡和炎症。有了dMRI和MEMRI，我们将能够 检查新生儿HI后广泛的病理事件。 低温是新生儿HI的标准治疗，但其保护机制不是 明白了据推测，低温可减少细胞肿胀、炎症和血管生成。 水肿，并且可能延迟伪正常化过程。在aim3中，前两个阶段开发的技术 然后，目的将被应用于表征用低温治疗的小鼠中的HI损伤，以定量地 描述其作用并阐明其神经保护机制。 我们希望该项目能扩展我们对病理学和诊断学之间关系的认识。 标志物，并阐明HI损伤和治疗性低温的机制。这 本项目中开发的信息和技术将有助于制定有效的干预战略 并在使用该模型或类似模型的研究中监测治疗反应。

Abstract Hypoxic ischemic (HI) insult damages both white matter and grey matter in infants and causes significant mortality and morbidity. To investigate the pathological mechanisms of neonatal HI injury and find satisfactory treatments, animal models of neonatal hypoxic ischemic injury have been established and widely used. In this project, novel in vivo magnetic resonance imaging on tissue microstructure and neuronal activity will be developed to examine the progression of HI injury and the effects of therapeutic hypothermia in a neonatal mouse model. In aim 1, we will examine the sensitivity of novel diffusion MRI (dMRI) techniques to tissue microstructural changes caused by HI injury. Preliminary results have shown that the proposed imaging techniques can more sensitively detect mild brain injuries than conventional dMRI techniques and is less susceptible to confounding pseudo-normalization of conventional dMRI signals. We will use histology and electron microscopy to determine the levels of cellular and subcellular structural changes and correlate quantitative measurements with dMRI signals, and use numerical simulations to understand the relationships between them. The knowledge will be used to optimize the imaging protocols to detect key structural changes after neonatal HI. In aim 2, we will examine injury using manganese-enhanced MRI (MEMRI). Previous studies have shown that the MEMRI contrasts reflect neuronal activity in the brain and can selectively enhance regions with apoptosis and inflammation after neonatal HI. In this aim, we will examine the sensitivity of MEMRI to loss of neuronal activity, apoptosis, and inflammation after neonatal HI. With both dMRI and MEMRI, we will be able to examine a broad range of pathological events after neonatal HI. Hypothermia is the standard care for newborns with neonatal HI, but its protective mechanisms are not clearly understood. It has been assumed that hypothermia reduces cell swelling, inflammation, and vasogenic edema, and may delay the pseudo-normalization process. In aim 3, the techniques developed in the first two aims will then be applied to characterize HI injury in mice treated with hypothermia to quantitatively characterize its effects and elucidate its neuroprotective mechanisms. We expect the project to extend our knowledge on the relationships between pathology and diagnostic markers in this mouse model, and shed light on the mechanisms of HI injury and therapeutic hypothermia. This information and techniques developed in this project will be useful to design effective strategies for intervention and to monitor treatment response in studies using this or similar models.