MR-Based Study of Hypomyelination by Lead Poisoning

描述（由申请人提供）：本项目的总体目标是建立磁共振微成像作为研究髓鞘形成毒理学的工具的有效性，并将其应用于铅中毒引起的髓鞘形成减少的研究。髓鞘形成是一个非常复杂的过程；髓鞘形成在不同的时间点开始，每个白质束的速率不同。因此，全面表征髓鞘形成状态，即使是正常状态，也不是一项简单的任务。这对髓鞘形成的毒理学评价提出了很大的挑战。在这个项目中，我们将使用离体高分辨率MRI和大鼠新生儿模型来表征髓鞘形成过程的时间和空间特征。使用这种技术将达到以下三个目的。

DESCRIPTION (provided by applicant): The overall goal of this project is to establish the usefulness of magnetic resonance microimaging as a tool to study myelination toxicology and apply it to investigate hypomyelination caused by lead poisoning. Myelination is a very complex process; myelination starts at the different time point with different rates for each white matter tract. As a result, comprehensive characterization of myelination status, even of the normal state, is not a straightforward task. This poses a great challenge for toxicological assessment of myelination. In this project, we will use the ex vivo high-resolution MRI and a rat neonate model to characterize the temporal and spatial profile of the myelination process. Using this technique following three aims will be pursued. Aim 1: Characterization of temporal and spatial profile of the normal rat myelination process using MRI and fixed brain samples. Hypothesis: "Ex vivo high-resolution MRI can reveal the dynamic process of myelination three-dimensionally in a tract-by-tract basis". The microimaging technique will be applied to a series of normal brain samples at different development stages to monitor the myelination process. The observed changes of MR parameters will be correlated with histology to confirm the hypothesis. Aim 2: Study of the myelination abnormality by high-dose lead administration. Hypothesis: "Ex vivo high-resolution MRI can sensitively and efficiently detect myelination abnormalities" Hypomyelination by lead uptake has been previously reported and our preliminary data show that MRI can sensitively detect the hypomyelination of specific white matter tracts. We will use this system to compare MRI findings and histology data and to validate the hypothesis. Aim 3: Study of the temporal, spatial, and dose profiles of the myelination abnormality by low-dose lead administration. Hypothesis: "Low-dose lead uptake induces the myelination abnormality, which is independent of malnutrition". Hypomyelination by lead uptake has been considered as one of the important developmental impairments by the lead uptake. However, to date, it has not been clear whether the observed hypomyelination is secondary to the concomitant malnutrition and weight loss. Using the MRI-based technique and normative database established under Aim 1 and 2, we will perform comprehensive myelination studies to examine the hypothesis