Axonal pathology during the course of multiple sclerosis

描述：这项提议是基于这样一个假设，即轴突损失是神经系统的一个重要组成部分。 不可逆的神经系统体征和症状的主要原因在多个 硬化症患者首席研究员设计了一系列 实验，以解决有关轴突损失和其他 多发性硬化斑块和两种动物对应物中的轴突病变 (Aims 1-3）;他还打算在目标4中评估少突胶质细胞瘤的状态， 多发性硬化斑块内和周围的前体细胞。多发性硬化 脊髓，几乎完全是死后的，将通过快速尸检获得; 将通过以下方法收集这些患者与对照组的轴突计数： 形态测量技术，并进行统计分析。类似 操作将在炎性脱髓鞘的动物模型上进行 和实验性脊髓损伤研究者在目标1中建议， 量化MS脊髓切片中的轴突、终末卵形体和髓鞘 用磷酸化和磷酸化的神经丝抗体免疫染色， 非磷酸化蛋白脂质蛋白和MHC II类分子通过 脱髓鞘斑块以及斑块周围的形态学分析 近端和远端轴突反应。这些测量将在急性 与慢性斑块进行比较，并与对照组进行比较。共焦 双标记荧光制剂的显微镜检查将是 这些数据。轴突损伤将与组织中的 N-乙酰基-天冬氨酸，采用HPLC法，在研究切片系列中 形态学上。将在大鼠脊髓中使用相同的方法（Aim 2）， 在第2、7、14、16和120天进行横切和检查 横切后。目的3是利用小鼠模型进行比较分析 慢性复发性EAE，已通过给药诱导 蛋白脂质蛋白的一部分。最后一系列实验（目标4） 将尝试描述分布特征并确定功能 急性和慢性炎症中少突胶质细胞前体细胞亚群 使用NG 2、PDGFar、GRO-α r、erbB抗体检测多发性硬化病变 2、3、4、P75加Trk A、p75减Trk A、fas和活化的半胱天冬酶3。

DESCRIPTION: This proposal is based on the hypothesis that axonal loss is the major cause of irreversible neurological signs and symptoms in multiple sclerosis patients. The principal investigator has designed a series of experiments to address fundamental questions regarding axonal loss and other axonal lesions in multiple sclerosis plaques and in two animal counterparts (Aims 1-3); he also intends in Aim 4 to assess the status of oligodendrocytic precursor cells in and around multiple sclerosis plaques. Multiple sclerosis spinal cord, almost exclusively postmortem, will be obtained by rapid autopsy; axonal counts from these patients versus controls will be collected by morphometric techniques and subjected to statistical analyses. Similar manipulations will be performed on animal models of inflammatory demyelination and experimental spinal cord trauma. The investigator proposes in Aim 1 to quantify axons, terminal ovoids, and myelin sheaths in MS spinal cord sections immunostained with antibodies to neurofilaments, both phosphorylated and non-phosphorylated, proteolipid protein and MHC class II molecules through a morphometric analysis of the demyelinative plaques, as well as periplaque proximal and distal axonal reactions. These measurements will be made in acute to chronic plaques and compared to each other and to controls. Confocal microscopy of double-labeled fluorescent preparations will be a major source of this data. The axonal lesions will be correlated with tissue levels of N-acetyl-aspartic acid, utilizing HPLC, in sections serial to the ones studied morphologically. This same approach will be used in rat spinal cord (Aim 2), which has been transected and examined at 2, 7, 14, 16, and 120 days post-transection. Aim 3 is to do a comparable analysis utilizing a mouse model of chronic relapsing EAE that has been induced through the administration of a portion of the proteolipid protein. The final series of experiments (Aim 4) will attempt to characterize the distribution and determine the functional subpopulations of oligodendrocytic precursor cells in acute and chronic multiple sclerosis lesions by using antibodies to NG2, PDGFar, GRO-ar, erbB 2,3,4, P75 plus Trk A, p75 minus Trk A, fas, and activated caspase 3.