Biomarkers and Pathogenesis of Multiple Sclerosis: From Mouse to Human

描述（由申请人提供）：这是一个新的项目项目，旨在扩大和延续一个高度整合的研究小组的长期合作研究，他们对理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多篇共同撰写的论文，研究了中枢神经系统炎症和白质损伤的潜在机制。总之，该小组开发了一种使用弥散张量成像（DTI）进行无创检测和分化轴突和髓鞘损伤的新方法，然后在动物模型中验证了该方法。在本PPG中，将采用无创DTI方法和先进的组织学检查侵袭性炎症细胞与中枢神经系统内驻留细胞之间的通讯以及单个核细胞浸润的血管周围调节。PPG的目标是了解中枢神经系统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年首批获得国家多发性硬化症协会合作多发性硬化症研究中心奖的三个中心之一。该奖项将于2008年冬季结束。Proj 1“评估白质损伤的MRI生物标志物”由SK Song指导，他的团队将使用三种白质损伤模型来确定CNS白质损伤的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来评估EAE的治疗效果和脊髓损伤的预后。项目2“CXCL12在中枢神经系统脱髓鞘疾病中的神经保护机制”由趋化因子在实验病毒模型和EAE中的作用的资深研究员R Klein主持。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转运，血管周围定位如何调节中枢神经系统自身免疫过程中的单个核细胞活化，以及CXCL12如何调节髓鞘再生。项目3“CNS与淋巴细胞相互作用调节炎症”由J Russell主持。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，而实质浸润反过来又对EAE的严重程度至关重要。利用他开发的动物模型，将测试DTI生物标志物的敏感性。中枢神经系统不同区域星形胶质细胞对各种细胞因子环境和Th1和Th17细胞运输的反应将使用gd增强MRI和DTI进行检查。项目4“定向扩散作为MS病理的窗口”，由a . Cross指导，将把项目1、2和3的发现转化为人类。将确定使用DTI识别活人大脑白质束和脊髓病理的可行性。

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.