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（MS）是一种中枢神经系统的炎症性和神经退行性疾病 由此无情的脱髓鞘和神经轴突损失是不可逆残疾的主要原因。测试 解决疾病的神经退行性成分的策略，试图阻止进展， 促进功能恢复，是MS转化研究的一个重要焦点。 用于监测疾病进展的生物标志物是这一努力的重大障碍。 神经影像学的最新进展提供了新的机会，开发和验证生物标志物， 神经退行性变作为诊断和监测工具的有价值的证据。为此，最近开展的工作 在范德比尔特大学医学中心，导致了两个创新的定量磁技术的发展， 共振成像（MRI）技术，即，选择性反转恢复定量磁化转移 成像（SIR-qMT）和使用球面平均技术（SMT）的扩散成像。SIRqMT和SMT 分别为髓鞘和轴突损伤的非侵入性定量提供了新的框架。 MS的几种动物模型目前可用于研究MS的不同临床和生物学特征。 疾病例如，髓鞘蛋白脂质蛋白（PLP）诱导的实验性过敏性脑脊髓炎 (EAE)类似于复发-缓解型MS表型（R-EAE），并作为一个有价值的模型来研究 复发、急性炎症和脱髓鞘/髓鞘再生的发展。相反，泰勒氏鼠 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了临床 以及进行性MS的病理特征，如脱髓鞘、慢性神经炎症和轴突损伤。 损伤，导致缓慢进展的残疾。这两个模型提供了关于以下方面的补充信息： MS的发展和演变，共同形成了一个理想的模型系统，以测试新疗法的潜力。 因此，我们假设从SIR-qMT和（表观） 从SMT获得的轴突体积分数（Vax）将提供髓鞘和轴突的早期和敏感的生物标志物 损伤，分别在两个小鼠模型的脑和脊髓中。 将在R-EAE、TMEV-IDD和年龄匹配的假手术中纵向进行脑和脊髓MRI。 处理的小鼠，使用组织学和行为分析来验证成像衍生的生物测定。短期目标 本研究的目的是在两种临床上不同的MS小鼠模型中应用SIR-qMT和SMT， 根据组织病理学和临床对应物验证PSR和Vax。我们研究的长期目标是 开发更有效和非侵入性的神经变性和修复生物标志物，可用于 研究MS的变化，无论是在动物模型和人类，在自然史研究和实验 临床试验