Biomarkers and Pathogenesis of MS: From Mouse to Human

描述(由申请人提供)：这是一个高产出计划项目的修订续签申请，“多发性硬化症的生物标记物和病理：从小鼠到人类”，包括三个项目，一个统计核心，一个动物模型/人类组织库核心和一个成像核心，重点是了解中枢神经系统炎症性自身免疫疾病，特别是多发性硬化症(MS)的发病机制。更好地了解MS进展的机制，以及轴突持续受损和脱落的原因，将有助于指导这种常见疾病的新疗法的开发。此外，迫切需要创新的方法来测量中枢神经系统炎症、脱髓鞘和轴突损伤，以及中枢神经系统修复，不仅要更好地了解人类多发性硬化症的发病机制，而且要加快测试新的治疗方法。在我们的头五年中实现了一项重大创新，我们开发了新的扩散基础光谱成像(DBSI)，我们现在建议最终验证并继续推进，以满足当前的需求。在最初评审者的鼓励和指导下，我们扩大了先前的重点，包括入侵的炎症细胞和中枢神经系统中的驻留细胞之间的通讯机制研究，导致血脑屏障完整性的丧失。 将使用最先进的成像方式。这三个P01项目的主题是与定义血脑屏障信号和免疫细胞进入之间的接口以及这如何影响持续性炎症损害的发展和轴突病理的目标相联系。后者尤其可能是进行性多发性硬化症的基础。每个项目都使用提供统计、动物模型/人体组织库、成像和行政支持的全部三个核心。总体目标是(1)利用动物模型、人体组织和多发性硬化症患者开发和测试白质损伤的新型尖端非侵入性和特异性MRI生物标志物；以及(2)研究和靶向血管通透性变化影响白细胞激活和进入中枢神经系统的机制。

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.