Biomarkers and Pathogenesis of Multiple Sclerosis: From Mouse to Human

多发性硬化症的生物标志物和发病机制：从小鼠到人类

• 批准号: 7827594
• 负责人: DOROTHY ANNE CROSS
• 金额: $ 2.7万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7827594
• 关键词: Animal Model; Astrocytes; Autoimmune Diseases; Award; Biological Markers; CNS autoimmunity; CXCL12 gene; Cells; Collaborations; Communication; Demyelinating Diseases; Detection; Diffusion Magnetic Resonance Imaging; Environment; Experimental Autoimmune Encephalomyelitis; Goals; Histology; Human; Infiltration; Inflammation; Inflammatory; Injury; Invaded; Laboratories; Life; Lymphocyte; Magnetic Resonance Imaging; Manuscripts; Mediating; Methods; Modeling; Mononuclear; Multiple Sclerosis; Mus; Myelin; Pathogenesis; Pathology; Patients; Regulation; Research; Research Personnel; Rodent; Role; Severities; Societies; Spinal Cord; Surrogate Endpoint; TNFRSF1A gene; Testing; Translating; Treatment Efficacy; Viral; Work; brain tract; chemokine; cytokine; imaging modality; interest; novel strategies; outcome forecast; programs; response; trafficking; white matter; white matter injury

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.

描述（由申请人提供）：这是一个新的计划项目，旨在扩大和延续高度整合的研究人员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。该小组过去的合作已产生 20 多篇共同撰写的手稿，研究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）进行无创检测和区分轴突和髓磷脂损伤的新方法，然后在动物模型中验证了该方法。在该 PPG 中，将通过非侵入性 DTI 方法和先进的组织学检查入侵炎症细胞和 CNS 中驻留细胞之间的通讯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（特别是 MS）的发病机制，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的团队是 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。该不可再生的 Syr 奖项将于 2008 年冬季结束。项目 1“评估多发性硬化症的 MRI 生物标志物” 《白质损伤》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 生物标志物的敏感性以及评估使用这些生物标志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 CNS 脱髓鞘疾病中的神经保护机制”由 R Klein 指导，R Klein 是一位研究趋化因子在实验病毒模型和 EAE 中的作用的资深研究员。 Proj 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核细胞转运至 CNS、血管周围定位如何在 CNS 自身免疫过程中调节单核细胞激活，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”由 J Russell 指导。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，而实质浸润又对 EAE 的严重程度至关重要。使用他开发的动物模型，将测试 DTI 生物标志物的敏感性。将使用 Gd 增强 MRI 和 DTI 检查不同 CNS 区域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。由 A. Cross 指导的项目 4“定向扩散性作为 MS 病理学的窗口”将把项目 1、2 和 3 的发现转化为人类。将确定使用 DTI 辨别活人大脑和脊髓白质束病理的可行性。