LOCALIZATION AND CHARACTERIZATION OF IRON DEPOSITS IN MULTIPLE SCLEROSIS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 在这个提议中，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MS重要特征的动物模型中的作用。将使用MS患者诊断中常用的MRI序列进行成像。使用MRI图像作为指导，将每个大脑切片2 mm厚，并使用快速扫描XRF（100微米光束）绘制新鲜面部的铁和其他丰富元素（钙，铜和锌）。通过SRS-XRF绘制多种元素的能力至关重要，因为初步数据显示MS病变锌含量低，活动性疾病区域铁含量高，铜含量也异常。将切除感兴趣的区域用于微探针分析和免疫病理学，并确定铁的化学形式。将与活动性疾病（小胶质细胞）相关的铁化学与可能由慢性脑静脉功能不全（CCSVI）引起的脑引流血管周围观察到的铁进行比较。CCSVI与许多类型的MS相关。在组织可用的情况下，将在10 K下从冷冻人脑组织切除的ROI收集铁K边缘光谱。在第二项研究中，结合MRI与快速扫描（50微米束）和微探针XRF，我们将映射铁在小鼠模型进行性MS。在这种小鼠模型中，脱髓鞘是由病毒感染。 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灶性脱髓鞘大鼠模型，研究多种金属在愈合过程中的作用。这是一个复发缓解型MS的模型，其中愈合过程和髓鞘再生可以随着时间的推移而进行。初步工作表明，一个20微米的毛细管光学将提供足够的流量和分辨率在这项研究中的初始映射。

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.