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.

项目概要 多发性硬化症 (MS) 是一种中枢神经系统炎症和神经退行性疾病 因此，持续的脱髓鞘和神经轴突损失是导致不可逆转的残疾的主要原因。 解决该疾病的神经退行性成分的策略，试图阻止疾病的进展和 促进功能恢复，是多发性硬化症转化研究的一个重要焦点，但缺乏合适的研究。 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为开发和验证生物标志物提供了新的机会 为此，最近开展的工作将神经退行性疾病作为诊断和监测工具的有价值的辅助手段。 范德比尔特大学医学中心领导了两种创新定量磁力的技术开发 磁共振成像（MRI）技术，即选择性反转恢复定量磁化转移 成像（SIR-qMT）和使用球均技术（SMT）的扩散成像。 分别为髓磷脂和轴突损伤的非侵入性定量提供了一个新的框架。 目前有多种多发性硬化症动物模型可用于研究多发性硬化症的不同临床和生物学特征 例如，髓鞘蛋白脂质蛋白（PLP）引起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)，可作为研究 MS 表型的有价值的模型。 复发、急性炎症和离线脱髓鞘/髓鞘再生的发展，泰勒氏小鼠。 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 以及进行性多发性硬化症的病理特征，例如脱髓鞘、慢性神经炎症和轴突 损伤，导致缓慢进展的残疾，这两个模型提供了有关的补充信息。 MS 的发展和进化共同形成了一个理想的模型系统来测试新疗法的潜力。 因此，我们追求从 SIR-qMT 导出的池饱和比 (PSR) 和（表观） SMT 衍生的轴突体积分数 (Vax) 将提供髓磷脂和轴突的早期且敏感的生物标志物 分别对两种小鼠模型的大脑和脊髓造成损伤。 脑和脊髓 MRI 将在 R-EAE、TMEV-IDD 和年龄匹配的假手术中纵向进行。 治疗小鼠，使用组织学和行为分析来验证成像衍生的生物识别技术。 本研究的目的是将 SIR-qMT 和 SMT 应用于两种临床不同的 MS 小鼠模型，以 根据组织病理学和临床单位验证 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退行性变和修复生物标志物，可用于 研究自然历史研究和实验过程中动物模型和人类 MS 的变化 临床试验。