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：
7276107
负责人：
SHENG-KWEI SONG
金额：
$ 36.95万
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/7276107
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 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

DESCRIPTION (provided by applicant): 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 (lambda-II, axial diffusivity) and perpendicular to (lambda-I, radial diffusivity) axonal tracts. We have previously proposed and validated that decreased lambda-II is associated with axonal injury and dysfunction, and increased lambda-I- is associated with myelin injury in mouse models of white matter injury. Therefore, a significant reduction in lambda-II 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.

描述（由申请人提供）：MS是中枢神经系统的慢性炎症性疾病，主要破坏了髓鞘。数十年来，MS也出现了轴突损失。原则上，炎症和脱髓鞘引起的功能不足可能是可逆的。相反，一旦超过补偿阈值，轴突和神经元的损害可能是不可逆的。因此，已经广泛推测轴突丧失是MS中不可逆神经系统损害的病理相关性。但是，在受到严重影响的患者的病变中，轴突丧失并不总是明显的。 MS的潜在机制的复杂性和异质性需要新的临时标记，以更准确地诊断和对疾病的更精确的治疗管理。在拟议的研究中，将使用MS动物模型提出并评估一种新的扩散张量成像（DTI）方法，用于在中枢神经系统（CNS）中无创检测白质（CNS）。翻译前验证将采用人类尸检中枢神经系统组织。通过扩散张量成像得出的定向扩散性描述了与（Lambda-II，轴向扩散性）平行的水运动，并垂直于（Lambda-I，径向扩散率）轴突段。我们以前已经提出并证实了降低的Lambda-II与轴突损伤和功能障碍有关，而Lambda-I-I-在白质损伤的小鼠模型中与髓磷脂损伤有关。因此，在MS患者中，CNS白质的Lambda-II或实验性自身免疫性脑脊髓炎（EAE）的LAMBDA-II显着降低将暗示轴突变性和长期预后不良。为了检验我们的假设，将通过在两种小鼠菌株中进行主动免疫来诱导EAE，以模拟MS（C57BL/6小鼠）和复发启动的MS（RRMS; SJL小鼠）的非恢复形式。我们预测，轴突损伤将与非恢复神经系统缺陷有关。这将发生在反映该模型的非隔离性质的C57BL/6小鼠中。在SJL小鼠中，早期轴突损伤将与神经功能缺陷急性峰值峰值后的不完全缓解相关，而轴突完整性将通过完全缓解保留。在这两种菌株中，轴突损伤的程度将与神经系统缺陷的急性峰值的持续时间紧密相关 - 大概是由急性炎症反应引起的。