Noninvasive Quantification of Axon Damage in EAE and MS

EAE 和 MS 中轴突损伤的无创定量

基本信息

批准号：
7360314
负责人：
SHENG-KWEI SONG
金额：
$ 36.9万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-15 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7360314
关键词：
Active Immunization Acute Affect Amino Acids Amyloid beta-Protein Precursor Animal Model Animals Anisotropy Attention Autopsy Axon Biological Preservation Brain Brain imaging C57BL/6 Mouse Central Nervous System Diseases Cessation of life Chronic Clinical Clinical Markers Data Defect Demyelinations Detection Diagnosis Diffusion Magnetic Resonance Imaging Disease Disease Management Disease remission Dose Effectiveness Electron Microscopy Encephalomyelitis Evaluation Event Exhibits Experimental Autoimmune Encephalomyelitis Financial compensation Formalin Functional disorder Future Hematoxylin and Eosin Staining Method Heterogeneity Histology Hour Human Image Immersion Investigative Technique Impairment Inflammation Inflammatory Inflammatory Response Injury Ink Knock-out Lesion Literature Luxol Fast Blue MBS Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measurement Methods Modeling Mouse Strains Multiple Sclerosis Mus Myelin Myelin Basic Proteins Myelin Sheath N-acetylaspartate Nature Neuraxis Neurologic Neurological outcome Neurons Outcome Outcome Assessment Pathologic Pathology Patients Peptides Phase Phenytoin Proteins Proteolipids Protocols documentation Protons Radial Recovery Recovery of Function Relapsing-Remitting Multiple Sclerosis Relative (related person)Reporting Research Design Research Personnel SJL Mouse Score Severities Signal Transduction Specimen Speed Spinal Cord Staining method Stains System Testing Therapeutic Therapeutic Intervention Time Tissues Translations Treatment Efficacy Validation Water Movements Weight base diffusion anisotropy disability drug discovery human study human tissue improved in vivo indexing injured mouse model neurofilament oligodendrocyte-myelin glycoprotein outcome forecast programs prospective sample fixation translational study white matter white matter injury

项目摘要

MS is a chronic inflammatory disease of the CNS with primary destruction of myelin sheaths. It has been known for decades that axonal loss also occurs in MS. In principle, the functional deficit induced by inflammation and demyelination may be reversible. In contrast, the damage to axons and neurons is likely to be irreversible once the threshold of compensation is exceeded. Thus, it has been widely speculated that axonal loss is the pathologic correlate of irreversible neurological impairment in MS. However, axonal loss is not always evident in lesions from patients who are severely affected. The complexity and heterogeneity of the underlying mechanisms of MS require new para-clinical markers for more accurate diagnosis and more precise therapeutic management of the disease. In the proposed studies, a new diffusion tensor imaging (DTI) based method for noninvasive detection of axonal damage in central nervous system (CNS) white matter will be presented and evaluated using animal models of MS. Pre-translational validation will employ human autopsy CNS tissues. The directional diffusivities derived by diffusion tensor imaging describe water movement parallel to (k\\, axial diffusivity) and perpendicular to (A,i, radial diffusivity) axonal tracts. We have previously proposed and validated that decreasedXy is associated with axonal injury and dysfunction, and increased^ is associated with myelin injury in mouse models of white matter injury. Therefore, a significant reduction inK\\ in CNS white matter in MS patients or in mice with experimental autoimmune encephalomyelitis (EAE) will be suggestive of axonal degeneration and a poor long-term prognosis. To test our hypothesis, EAE will be induced by active immunization in two mouse strains to mimic progressive, non-remitting forms of MS (C57BL/6 mice) and relapsing-remitting MS (RRMS; SJL mice). We predict that axonal damage will be associated with non-remitting neurological defects. This will occur early in C57BL/6 mice reflecting this model's non-remitting nature. In SJL mice, early axonal damage will correlate with incomplete remission following acute peaking of neurological deficits, whereas axonal integrity will be retained with full remissions. In both strains, the extent of axonal damage will closely relate to the duration of the acute peaking of neurological deficits - presumably caused by acute inflammatory responses.

MS是中枢神经系统的慢性炎症性疾病，主要破坏髓鞘。它有几十年来，MS也出现了轴突丢失。原则上，由炎症和脱髓鞘可能是可逆的。相反，轴突和神经元的损害可能一旦超过薪酬阈值，就不可逆转。因此，已经广泛推测轴突丧失是MS中不可逆性神经系统障碍的病理相关性。但是，轴突损失是在受到严重影响的患者病变中并不总是明显的。复杂性和异质性 MS的基本机制需要新的Para-Cla-Claical标记，以更准确地诊断和更多该疾病的精确治疗管理。在拟议的研究中，新的扩散张量成像（DTI）非侵入性检测中枢神经系统（CNS）白色的方法物质将使用MS的动物模型进行和评估。预先验证将采用人体尸检CNS组织。通过扩散张量成像得出的定向扩散性描述了与平行于（k \\，轴向扩散率）和垂直于（a，i，径向扩散率）轴突段。我们以前提出过并验证了减少与轴突损伤和功能障碍有关，并且增加^ IS 与白质损伤的小鼠模型中的髓磷脂损伤相关。因此，大量减少墨水\\ 在MS患者或具有实验性自身免疫性脑脊髓炎（EAE）的小鼠中的CNS白质中暗示轴突变性和长期预后不佳。为了检验我们的假设，EAE将通过两种小鼠菌株的主动免疫引起EAE。 MS（C57BL/6小鼠）和复发复发的MS（RRMS; SJL小鼠）的渐进性，非恢复形式。我们预测轴突损伤将与非复制神经系统缺陷有关。这会早点发生在C57BL/6小鼠中，反映了该模型的非复制性质。在SJL小鼠中，早期轴突损伤将相关神经系统缺陷的急性峰值后，由于不完全缓解，而轴突完整性将为全力以赴。在这两种菌株中，轴突损伤的程度将与持续时间紧密相关神经缺陷的急性峰 - 大概是由急性炎症反应引起的。