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 ? ?

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Kirshner, Annette G
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Johns Hopkins University
Schools of Medicine
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