LOCALIZATION AND CHARACTERIZATION OF IRON DEPOSITS IN MULTIPLE SCLEROSIS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 在这项建议中，我们将同步加速器X射线荧光(XRF)和磁共振成像(MRI)的独特能力与经典免疫病理学相结合，以阐明铁沉积在人类多发性硬化症(MS)和概括人类多发性硬化症重要特征的动物模型中的作用。首先，将使用诊断多发性硬化症患者常用的MRI序列对受MS影响和未受影响的人类尸检脑片进行成像。以核磁共振图像为指导，每个大脑将被切成2毫米厚的切片，新鲜的面部将使用快速扫描XRF(100微米光束)绘制铁和其他丰富元素(钙、铜和锌)的地图。通过SRS-XRF绘制多元素图的能力是至关重要的，因为初步数据显示，MS病变的锌含量低，活动性疾病的区域铁含量高，铜也异常。感兴趣的区域将被切除，用于微探针分析和免疫病理学，并确定铁的化学形态。与活动性疾病(小胶质细胞)有关的铁化学将与可能由慢性脑静脉功能不全(CCSVI)引起的引流大脑的血管周围的铁进行比较。CCSVI与多种类型的多发性硬化症相关联，在有组织可用的情况下，将从冰冻的人脑组织切除的ROI中收集10K下的铁K边光谱。在第二项结合了MRI、快速扫描(50微米光束)和微探针XRF的研究中，我们将在进行性多发性硬化症的小鼠模型中定位铁。在第三项研究中，我们将使用脂多糖诱导的大脑和坐骨神经局部脱髓鞘的大鼠模型，研究多种金属在愈合过程中的作用。这是一种复发缓解型多发性硬化症的模型，其中愈合过程和重新髓鞘形成可以随着时间的推移而进行。初步工作表明，20微米的毛细光学系统将为本研究的初始测绘提供足够的通量和分辨率。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In this proposal we combine the unique capabilities of synchrotron x-ray fluorescence (XRF) and magnetic resonance imaging (MRI) with classical immunopathology to elucidate the role of iron deposits in human multiple sclerosis (MS) and in animal models that recapitulate important features of human MS. First, thick human autopsy brain slices, both MS affected and unaffected, will be imaged using MRI sequences commonly used in the diagnosis of MS patients. Using the MRI image as a guide, each brain will be sliced 2 mm thick and the fresh face will be mapped for iron and other abundant elements (calcium, copper and zinc) using rapid-scanning XRF (100 micron beam). The ability to map multiple elements, by SRS-XRF, is crucial because preliminary data shows that MS lesions are low in zinc, regions of active disease are high in iron and copper is also abnormal. Regions of interest will be excised for microprobe analysis and immunopathology and to determine the chemical form of iron. Iron chemistry associated with active disease (microglia) will be compared with iron seen around vessels draining the brain that may result from chronic cerebral venous insufficiency (CCSVI). CCSVI is linked to many types of MS. Where tissue is available, iron K-edge spectra will be collected at 10K from ROI excised from frozen human brain tissue. In a second study combining MRI with rapid scanning (50 micron beam) and microprobe XRF, we will map iron in a mouse model of progressive MS. In this murine model, demyelination is produced by viral infection. In a third study we will examine the role of multiple metals in the healing process using a rat model of focal demyelination in the brain and sciatic nerve induced by lipopolysaccharide. This is a model of relapsing remitting MS in which the healing process and remyelination can be followed over time. Preliminary work shows that a 20 micron capillary optic will provide the sufficient flux and resolution for initial mapping in this study.