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：
7755369
负责人：
SHENG-KWEI SONG
金额：
$ 36.53万
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 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7755369
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 Severities Signal Transduction Specimen Speed Spinal Cord Staining method Stains System Testing Therapeutic Therapeutic Intervention Time Tissues Translations Treatment Efficacy Validation Water Movements Weight axonal degeneration base diffusion anisotropy disability drug discovery human tissue improved in vivo indexing inflammatory marker 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 是一种中枢神经系统慢性炎症性疾病，以髓鞘原发性破坏为特征。它有几十年来人们就知道轴突丢失也发生在多发性硬化症中。原则上，由以下原因引起的功能缺陷炎症和脱髓鞘可能是可逆的。相反，轴突和神经元的损伤可能会一旦超过赔偿门槛，则不可逆转。因此，人们普遍猜测轴突损失是多发性硬化症不可逆神经功能损伤的病理相关性。然而，轴突损失是在受到严重影响的患者的病变中并不总是很明显。的复杂性和异质性 MS 的潜在机制需要新的临床旁标记物以实现更准确的诊断和更多疾病的精确治疗管理。在拟议的研究中，一种新的扩散张量成像基于 DTI 的无创检测中枢神经系统 (CNS) 轴突损伤的方法将使用 MS 动物模型来呈现和评估物质。翻译前验证将采用人体尸检中枢神经系统组织。由扩散张量成像得出的方向扩散率描述了平行于（k\\，轴向扩散率）并垂直于（A，i，径向扩散率）轴突束。我们之前已经提出过并证实 Xy 减少与轴突损伤和功能障碍相关，而 Xy 增加则与轴突损伤和功能障碍相关。与白质损伤小鼠模型中的髓磷脂损伤相关。因此，K\\ 多发性硬化症患者或患有实验性自身免疫性脑脊髓炎 (EAE) 的小鼠的中枢神经系统白质中提示轴突变性和长期预后不良。为了检验我们的假设，两种小鼠品系通过主动免疫来模拟 EAE 进行性、非缓解型 MS（C57BL/6 小鼠）和复发缓解型 MS（RRMS；SJL 小鼠）。我们预测轴突损伤将与非缓解性神经缺陷相关。这会很早就发生在 C57BL/6 小鼠中，反映了该模型的非缓解性质。在 SJL 小鼠中，早期轴突损伤与神经功能缺损急性达到峰值后未完全缓解，而轴突完整性将受到影响完全缓解后保留。在这两种菌株中，轴突损伤的程度与轴突损伤的持续时间密切相关。神经功能缺损的急性峰值——可能是由急性炎症反应引起的。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CXCR7 antagonism prevents axonal injury during experimental autoimmune encephalomyelitis as revealed by in vivo axial diffusivity.

体内轴向扩散性表明，CXCR7 拮抗作用可防止实验性自身免疫性脑脊髓炎期间的轴突损伤。

DOI：
发表时间：
2011
期刊：
影响因子：
0
作者：
Cruz;Chen, Ying;Kim, Joong Hee;Dorsey, Denise;Song, Sheng;Klein, Robyn S
通讯作者：
Klein, Robyn S

Diffusion tensor imaging detects axonal injury and demyelination in the spinal cord and cranial nerves of a murine model of globoid cell leukodystrophy.

弥散张量成像可检测球状细胞脑白质营养不良小鼠模型的脊髓和颅神经的轴突损伤和脱髓鞘。

DOI：
发表时间：
2009-12
期刊：
影响因子：
2.9
作者：
Hofling, A Ale;Kim, Joong Hee;Fantz, Corinne R;Sands, Mark S;Song, Sheng
通讯作者：
Song, Sheng

Evolving Wallerian degeneration after transient retinal ischemia in mice characterized by diffusion tensor imaging.

以弥散张量成像为特征的小鼠短暂性视网膜缺血后演变的沃勒氏变性。

DOI：
发表时间：
2008-03-01
期刊：
影响因子：
5.7
作者：
Sun, Shu;Liang, Hsiao;Cross, Anne H;Song, Sheng
通讯作者：
Song, Sheng

Radial diffusivity predicts demyelination in ex vivo multiple sclerosis spinal cords.

径向扩散率预测离体多发性硬化症脊髓的脱髓鞘。

DOI：
发表时间：
2011-04-15
期刊：
影响因子：
5.7
作者：
Klawiter, Eric C;Schmidt, Robert E;Trinkaus, Kathryn;Liang, Hsiao;Budde, Matthew D;Naismith, Robert T;Song, Sheng;Cross, Anne H;Benzinger, Tammie L
通讯作者：
Benzinger, Tammie L

"A new imaging modality to non-invasively assess multiple sclerosis pathology".

“一种新的非侵入性评估多发性硬化症病理学的成像方式”。