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，旨在扩展和延续一个高度整合的研究人员群体的长期合作研究，这些研究人员对了解CNS自身免疫性有着共同的兴趣。该小组过去的合作已经导致了20多篇共同撰写的手稿，研究CNS炎症和白色损伤的潜在机制。总的来说，该小组开发了一种新的方法，使用扩散张量成像（DTI）进行非侵入性检测和区分轴突和髓鞘损伤，然后在动物模型中验证该方法。在该PPG中，将采用非侵入性DTI方法和先进的组织学检查CNS中侵入性炎症细胞和驻留细胞之间的通信以及单核细胞浸润的血管周围调节。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损伤的DTI生物标志物。PPG的几位研究人员组成了一个团队，该团队是2003年获得国家MS协会合作MS研究中心奖的前三个中心之一。这个Syr奖，不可再生的奖项将于2008年冬季结束。项目1“评估白色损伤的MRI生物标志物”由SK Song指导，其团队将使用三种白色损伤模型来确定CNS白色损伤的MRI生物标志物的敏感性，并评估这些生物标志物作为替代终点的使用，以评估EAE的治疗效果和SCI的预后。项目2“CXCL12在CNS脱髓鞘疾病中的神经保护机制”由R Klein指导，他是实验病毒模型和EAE中趋化因子作用的公认研究员。项目2将确定CXCL12介导的血管周围定位如何调节啮齿动物和人类自身免疫性疾病中单核细胞向CNS的运输，血管周围定位如何调节CNS自身免疫过程中单核细胞活化，以及CXCL12如何调节髓鞘再生。项目3“中枢神经系统和淋巴细胞相互作用调节炎症”是由J罗素。他的实验室最近的工作发现，星形胶质细胞的TNFR1反应是促进实质浸润的关键，而实质浸润又是EAE严重程度的关键。使用他开发的动物模型，将测试DTI生物标志物的灵敏度。将使用Gd增强MRI和DTI检查不同CNS区域中的星形胶质细胞对各种细胞因子环境以及Th1和Th17细胞运输的反应。项目4“定向扩散率作为MS病理学的窗口”，由A。克罗斯将把项目1、2和3的发现翻译给人类。将确定使用DTI来辨别活体人类大脑和脊髓的白色物质束中的病理的可行性。

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.