Biomarkers and Pathogenesis of MS: From Mouse to Human

描述（由申请人提供）：这是一个高生产力计划项目“MS的生物标志物和发病机制：从小鼠到人类”的修订后的更新申请，该项目由三个项目组成，一个统计核心，一个动物模型/人体组织库核心和一个成像核心，重点是了解CNS炎性自身免疫性疾病，特别是多发性硬化症（MS）的发病机制。更好地理解MS进展的机制，以及持续轴突损伤和脱落的基础将有助于指导这种常见疾病的新疗法的开发。此外，迫切需要测量CNS炎症、脱髓鞘和轴突损伤以及CNS修复的创新方法，不仅为了更好地理解人类MS发病机制，而且为了加速新疗法的测试。在我们的第一个五年里，我们开发了新型扩散基光谱成像（DBSI），实现了一项重大创新，我们现在建议明确验证并继续发展以满足当前的需求。在最初的评论者的鼓励和指导下，我们扩大了我们之前的重点，包括CNS中入侵的炎性细胞和驻留细胞之间的通信机制研究，导致血脑屏障完整性的丧失。 将使用最先进的成像模式。这三个P01项目在主题上与定义血脑屏障信号传导和免疫细胞进入之间的界面以及这如何影响持续性炎症病变和轴突病变的发展的目标相关联。每个项目都使用所有三个核心，提供统计，动物模型/人体组织库，成像和行政支持。总体目标是（1）使用动物模型、人体组织和MS患者开发和测试白色损伤的新型尖端非侵入性和特异性MRI生物标志物;（2）解决和靶向血管通透性变化影响白细胞活化和进入CNS的机制。

DESCRIPTION (provided by applicant): This is a revised renewal application for a highly productive Program Project, "Biomarkers and Pathogenesis of MS: From Mouse to Human," comprised of three projects, a Statistical Core, an Animal Model/Human Tissue Bank Core and an Imaging Core that are focused on understanding mechanisms of pathogenesis of CNS inflammatory autoimmune disorders, especially multiple sclerosis (MS). Better understanding of the mechanisms of MS progression, and what underlies the continued axonal damage and drop-out would help guide development of new therapeutics for this common disease. Additionally, an urgent need exists for innovative methods to measure CNS inflammation, demyelination and axonal injury, as well as CNS repair, not only to better understand human MS pathogenesis, but also to expedite testing of novel therapeutics. A major innovation was achieved during our first five years with our development of the novel Diffusion Basis Spectrum Imaging (DBSI) which we now propose to definitively validate and carry forward to address current needs. Following encouragement and guidance from initial reviewers, we expanded our prior focus to encompass mechanistic studies of the communication between the invading inflammatory cells and resident cells in the CNS, leading to loss of blood-brain barrier integrity. State-of-the-art imaging modalities will be used. The three P01 projects are linked thematically with the goals of defining the interface between blood-brain barrier signaling and immune cell entry and how this impacts the development of persistent inflammatory lesions, and axonal pathologies. The latter, in particular, may underlie progressive MS. Each project uses all three Cores that provide statistical, animal model/human tissue bank, imaging and administrative support. Overall objectives are to (1) develop and test novel cutting edge noninvasive and specific MRI biomarkers of white matter injuries using animal models, human tissues, and MS patients; and (2) to address and target the mechanisms by which changes in vascular permeability impact leukocyte activation and entry into CNS.