Longitudinal Measurement of Neurodegeneration in two Murine Models of Multiple Sclerosis: A Clinical and Histopathologic Validation Study

两种多发性硬化症小鼠模型神经变性的纵向测量：临床和组织病理学验证研究

• 批准号: 10328569
• 负责人: Francesca Rosaria Bagnato
• 金额: $ 19.15万
• 依托单位: DARTMOUTH-HITCHCOCK CLINIC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328569
• 关键词: Academic Medical Centers; Acute; Address; Age; Animal Model; Animals; Area; Axon; Behavioral; Biological; Biological Markers; Biological Models; Biometry; Blood - brain barrier anatomy; Brain; Cells; Central Nervous System Diseases; Chronic; Classification; Clinical; Clinical Research; Clinical Trials; Data; Demyelinating Diseases; Demyelinations; Development; Diagnostic; Diffusion; Disease; Disease Progression; Disease model; Encephalitis Viruses; Evolution; Experimental Autoimmune Encephalomyelitis; Experimental Models; Goals; Histology; Human; Image; Imaging Techniques; Immunization; Individual; Infiltration; Inflammation; Inflammatory; Injury; Investigational Therapies; Lesion; Magnetic Resonance Imaging; Measurable; Measurement; Measures; Medical; Modeling; Monitor; Mononuclear; Multiple Sclerosis; Mus; Myelin; Myelin Proteolipid Protein; Natural History; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Normal tissue morphology; Outcome Measure; Pathologic; Patients; Peptides; Phenotype; Physics; Property; Recovery; Recovery of Function; Relapse; Relapsing-Remitting Multiple Sclerosis; Research; SJL Mouse; Specificity; Spinal Cord; System; TMEV; Techniques; Testing; Time; Translational Research; Validation; Walking; Work; axon injury; clinical translation; clinically relevant; disability; imaging biomarker; in vivo; innovation; mouse model; multiple sclerosis treatment; neuroimaging; neuroinflammation; novel; novel therapeutics; physically handicapped; pre-clinical; preclinical study; remyelination; repaired; reparative process; tissue degeneration; tool; validation studies

PROJECT SUMMARY Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system whereby relentless demyelination and neuroaxonal loss are the primary cause of irreversible disability. Testing strategies to address the neurodegenerative component of the disease, in an attempt to halt the progression and promote functional recovery, is a significant focus of translational research in MS. However, a lack of suitable biomarkers to monitor disease progression is a significant impediment to this effort. Recent advances in neuroimaging offer novel opportunities to develop and validate biomarkers of neurodegeneration as valuable adjuncts to diagnostic and monitoring tools. To this end, recent work performed at Vanderbilt University Medical Center led to the technical development of two innovative quantitative magnetic resonance imaging (MRI) techniques, i.e., the selective inversion recovery quantitative magnetization transfer imaging (SIR-qMT) and the diffusion imaging using the spherical mean technique (SMT). SIRqMT and SMT provide a novel framework for non-invasive quantification of myelin and axonal injury, respectively. Several animal models of MS are currently available to study different clinical and biological features of the disease. For example, the myelin proteolipid protein (PLP)-induced experimental allergic encephalomyelitis (EAE) resembles the relapsing-remitting MS phenotype (R-EAE) and serves as a valuable model to study the development of relapses, acute inflammation and demyelination/remyelination. Conversely, the Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) mouse model uniquely reproduces clinical and pathological features of progressive MS, such as demyelination, chronic neuroinflammation, and axonal damage, leading to slowly progressing disability. The two models provide complementary information regarding MS development and evolution and together form an ideal model system to test the potentials of novel therapies. Accordingly, we hypothesize that the pool saturation ratio (PSR) derived from SIR-qMT and the (apparent) axonal volume fraction (Vax) derived from SMT will provide early and sensitive biomarkers of myelin and axonal injury, respectively, in the brain and spinal cord of the two murine models. Brain and spinal cord MRIs will be longitudinally performed in R-EAE, TMEV-IDD and age-matched sham- treated mice, using histology and behavioral analysis to validate imaging derived biometrics. The short-term goal and objective of this study are to apply SIR-qMT and SMT in two clinically distinct mouse models of MS to validate PSR and Vax against histopathologic and clinical counterparts. The long-term goal of our research is to develop more effective and non-invasive biomarkers of neurodegeneration and repair that can be used to investigate changes of MS, both in animal models and humans, during natural history studies and experimental clinical trials.

项目摘要 多发性硬化症（MS）是中枢神经系统的炎症和神经退行性疾病 因此，远程脱髓鞘和神经乳房丧失是不可逆转的残疾的主要原因。测试 解决该疾病的神经退行性成分的策略，以阻止进展和 促进功能恢复是MS转化研究的重要重点。但是，缺乏合适的 监测疾病进展的生物标志物是这项工作的重大阻碍。 神经影像学的最新进展为开发和验证生物标志物提供了新的机会 神经变性是诊断和监测工具的宝贵辅助手段。为此，最近的工作进行了 在范德比尔特大学医学中心，导致了两个创新定量磁的技术开发 共振成像（MRI）技术，即选择性反演恢复定量磁化转移 成像（SIR-QMT）和使用球形平均技术（SMT）的扩散成像。 SirQMT和SMT 分别为髓磷脂和轴突损伤的非侵入性定量提供了新的框架。 目前可以使用几种MS动物模型来研究不同的临床和生物学特征 疾病。例如，髓磷脂蛋白脂蛋白（PLP）诱导的实验性过敏性脑脊髓炎 （EAE）类似于复发的MS表型（R-EAE），并作为研究的宝贵模型 继电器的发展，急性炎症和脱髓鞘/再生。相反，Theiler的鼠 脑脊髓炎病毒诱导的脱髓鞘疾病（TMEV-IDD）小鼠模型独特地再现临床 渐进式MS的病理特征，例如脱髓鞘，慢性神经炎症和轴突 损坏，导致慢慢发展的残疾。这两种模型提供了有关的完整信息 MS开发和进化，并共同形成了一个理想的模型系统，以测试新疗法的潜力。 据此，我们假设池饱和比（PSR）衍生自SIR-QMT和（表观） 源自SMT的轴突体积分数（VAX）将提供髓磷脂和轴突的早期和敏感的生物标志物 在两个鼠模型的大脑和脊髓中分别受伤。 脑和脊髓MRI将在R-EAE，TMEV-IDD和年龄匹配的假手术中进行纵向进行 使用组织学和行为分析处理的小鼠以验证成像得出的生物识别技术。短期目标 这项研究的目的是将SIR-QMT和SMT应用于MS的两个临床不同的小鼠模型 验证PSR和VAX针对组织病理学和临床对应物进行验证。我们研究的长期目标是 开发更有效和无创的神经变性和修复生物标志物，可用于 在自然史研究和实验性研究中，研究动物模型和人类中MS的变化 临床试验。