Axonal pathology during the course of multiple sclerosis

描述：这一建议是基于这样的假设，即轴突损失是 多发性骨髓瘤不可逆神经体征和症状的主要原因 硬化症患者。首席调查员设计了一系列 解决有关轴突丢失和其他基本问题的实验 多发性硬化症斑块和两种动物对应的轴突损害 (目标1-3)；他还打算在目标4中评估少突胶质细胞症的状况 多发性硬化症斑块及其周围的前体细胞。多发性硬化症 脊髓，几乎完全是死后的，将通过快速尸检获得； 这些患者与对照组的轴突计数将通过以下方式收集 形态测量技术，并进行统计分析。类似 将在炎性脱髓鞘动物模型上进行手法治疗 和实验性脊髓损伤。调查员在目标1中提议 MS脊髓切片中轴突、终末卵泡和髓鞘的定量 免疫组织化学染色神经细丝抗体，磷酸化和 非磷酸化的蛋白脂蛋白和MHC II类分子 脱髓鞘斑块及其周围斑块的形态计量分析 近端和远端轴突反应。这些测量将在紧急情况下进行 对慢性斑块进行比较，并与对照组进行比较。共焦 双标记荧光制剂的显微镜将是主要的来源 这些数据。轴索损伤将与组织水平相关 N-乙酰天冬氨酸，利用高效液相色谱法，在与所研究的部分连续的部分中 从形态上看。同样的方法将用于大鼠脊髓(目标2)， 在第2、7、14、16和120天进行横切和检查 横断术后。目标3是利用老鼠模型进行可比性分析 慢性复发性EAE是通过给药一种 蛋白质脂蛋白的一部分。最后一系列实验(目标4) 将尝试确定分布的特征并确定功能 急、慢性少突胶质前体细胞亚群的研究 NG2、PDGFar、Gro-AR、erbB抗体在多发性硬化病变中的应用 2，3，4，p75+Trk A，p75减去Trk A，fas，激活的caspase 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.