Biomarkers and Pathogenesis of Multiple Sclerosis: From Mouse to Human

描述(由申请人提供)：这是一个新的计划项目，旨在扩大和保持一个高度整合的研究小组的长期合作研究，这些研究人员对了解中枢神经系统自身免疫有共同的兴趣。该小组过去的合作导致了20多篇共同撰写的手稿，调查了中枢神经系统炎症和白质损伤的潜在机制。该小组共同开发了一种使用扩散张量成像(DTI)对轴突和髓鞘损伤进行非侵入性检测和区分的新方法，并在动物模型中验证了该方法。在这个PPG中，侵袭性炎症细胞和CNS内驻留细胞之间的联系以及单个核细胞浸润的血管周围调节将用非侵入性DTI方法和先进的组织学来检查。PPG的目标是了解CNS自身免疫的发病机制，特别是MS，并评估动物模型和患者中损伤的DTI生物标记物。PPG的几名调查人员组成了一个团队，该团队是2003年获得全国MS协会协作MS研究中心奖的首批三个中心之一。本次SYR，不可再生奖将于2008年冬季结束。项目1《评估脑白质损伤的MRI生物标记物》由SK Song指导，他的团队将使用三种白质损伤模型来确定中枢神经系统白质损伤的MRI生物标记物的敏感性，并评估这些生物标记物作为替代终点来评估EAE的治疗效果和SCI的预后。项目2《CXCL12在中枢神经系统脱髓鞘疾病中的神经保护机制》是由R Klein指导的，他是一位研究趋化因子在实验性病毒模型和EAE中的作用的知名研究员。项目2将确定在啮齿动物和人类自身免疫性疾病中，CXCL12介导的血管周围定位如何调节单个核细胞向中枢神经系统的运输，血管周围定位如何调节中枢神经系统自身免疫过程中单个核细胞的激活，以及CXCL12如何调节再髓鞘形成。项目3“中枢神经系统和淋巴细胞相互作用调节炎症”由J·罗素执导。他的实验室最近的研究发现，星形胶质细胞的TNFR1反应是促进实质渗透的关键，而实质渗透又是EAE严重程度的关键。使用他开发的动物模型，将测试DTI生物标记物的敏感性。不同中枢神经系统区域的星形胶质细胞对不同细胞因子环境的反应以及Th1和Th17细胞的运输将使用Gd增强MRI和DTI进行检测。A·克罗斯执导的项目4《作为多发性硬化症病理的窗口的定向扩散性》将把项目1、2和3的发现转化为人类。使用DTI来识别活人大脑和脊髓白质束中的病理的可行性将被确定。

DESCRIPTION (provided by applicant): This is a new Program Project to expand and perpetuate the long-standing collaborative research of a highly integrated group of investigators with common interest in understanding CNS autoimmunity. Past collaborations of this group have led to more than 20 co-authored manuscripts investigating the underlying mechanisms of CNS inflammation and white matter injury. Collectively, the group developed a novel approach to use diffusion tensor imaging (DTI) for noninvasive detection and differentiation of axonal and myelin damage and then validated the method in animal models. In this PPG, communication between the invading inflammatory cells and resident cells in the CNS and the perivascular regulation of mononuclear cell infiltration will be examined with noninvasive DTI methods and with advanced histology. The PPG goals are to understand the pathogenesis of CNS autoimmunity, in particular MS, and assess the DTI biomarkers of injury in both animal models and patients. Several of the PPG investigators comprised a team that was one of the first three centers to receive the National MS Society's Collaborative MS Research Center award in 2003. This Syr, non-renewable Award will end in Winter 2008. Proj 1 "Assessing MRI Biomarkers of White Matter Injury" is directed by SK Song, whose team will use three models of white matter injury to determine the sensitivity of the MRI biomarkers of CNS white matter injury and assess the use of these biomarkers as the surrogate endpoint to evaluate therapeutic efficacy of EAE and prognosis of SCI. Proj 2 "Neuroprotective mechanisms of CXCL12 in CNS demyelinating diseases" is directed by R Klein, an established researcher on roles of chemokines in experimental viral models and EAE. Proj 2 will determine how CXCL12-mediated perivascular localization regulates mononuclear cell trafficking into CNS in both rodent and human autoimmune diseases, how perivascular localization regulates mononuclear cell activation during CNS autoimmunity, and how CXCL12 regulates remyelination. Proj 3 "CNS and lymphocyte interactions regulating inflammation" is directed by J Russell. Recent work from his laboratory has found that TNFR1 responses of astrocytes are key in promoting infiltration of the parenchyma which is in turn critical for EAE severity. Using animal models he has developed, the sensitivity of DTI biomarkers will be tested. Astrocyte responses in different CNS regions to a variety of cytokine environments and Th1 and Th17 cell trafficking will be examined using Gd-enhanced MRI and DTI. Proj 4 "Directional Diffusivity as a Window into the Pathology of MS," directed by A. Cross, will translate findings from Projects 1, 2, and 3 to humans. The feasibility of using DTI to discern pathology in the white matter tracts of brains and spinal cords of living humans will be determined.