Validating diffusion MRI biomarkers of inflammation and axon pathologies in EAE

验证 EAE 中炎症和轴突病理的扩散 MRI 生物标志物

基本信息

批准号：
8826186
负责人：
SHENG-KWEI SONG
金额：
$ 20.53万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-25 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8826186
关键词：
Abate Acute Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Axon Axonal Transport Biological Markers Biopsy Blinded C57BL/6 Mouse Central Nervous System Diseases Cerebrospinal Fluid Chronic Chronic Disease Clinic Clinical Clinical Trials Confidential Information Data Defect Demyelinating Diseases Demyelinations Diffusion Diffusion Magnetic Resonance Imaging Disease Disease Progression Evolution Experimental Autoimmune Encephalomyelitis Experimental Designs FDA approved Fiber Functional disorder Funding Goals Histologic Human Immunization Immunohistochemistry Impairment Individual Inflammation Inflammatory Injection of therapeutic agent Injury Intervention Limb structure Long-Term Effects Magnetic Resonance Imaging Manganese Measurement Measures Modeling Monitor Multiple Sclerosis Mus Myelin Nerve Fibers Neuraxis Neurologic Neurons Optic Nerve Optic Neuritis Oral Outcome Measure Pathogenesis Pathology Peptides Pharmaceutical Preparations Placebos Progressive Disease Public Health Radial Relapse Relapsing-Remitting Multiple Sclerosis Reporting Role Severities Spinal Cord Spinal Cord Tract Staging Testing Time Tissues Translations Treatment Efficacy Validation Vision Visual Visual Acuity Water axon injury base disability functional disability functional restoration imaging modality in vivo inflammatory marker myelin degeneration novel prevent programs research study spectrograph spinal cord white matter therapeutic target white matter

项目摘要

public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. We previously demonstrated that diffusion tensor imaging (DTI) successfully detects axon and myelin injury through decreased axial diffusivity (λ║, parallel to the white-matter tract) and increased radial diffusivity (λ, perpendicular to the white-matter tract) in animal models of central nervous system (CNS) diseases and injuries. During the initial Program Project funding period, we identified confounding factors, such as inflammation and tissue loss, causing misinterpretation of DTI-detected axonal pathologies. Thus, we developed a novel diffusion basis spectrum imaging (DBSI) to detect, differentiate, and quantify the extent of inflammation, and axon/myelin injury (Wang et al. 2011). In this PPG renewal, in vivo DBSI will be used to document the evolution of inflammation, axonal injury, and demyelination in optic nerve and spinal cord white-matter tracts in murine EAE, correlating with neurological impairment. DBSI-determined pathologies will be correlated with immunohistochemistry (IHC) during the course of EAE to validate DBSI injury markers. Functional impairment will be correlated with individual and/or combinations of axonal pathologies determined by DBSI and IHC to ascertain which best corresponds to clinical impairments. To explore the use of DBSI as an endpoint for clinical trials, the effect of FTY720 treatment on functional impairment in EAE will be correlated with DBSI-determined axonal pathologies in optic nerve and spinal cord tracts and confirmed by IHC. In addition, we will use both DBSI and the widely-reported manganese enhanced MRI to concomitantly assess the anterograde axonal transport rate of optic nerve in control vs. EAE mice to determine the relationship between axonal transport dysfunction and DBSI-determined axonal pathologies. This would allow an opportunity to delineate whether inflammation or axonal injury of optic nerve underlies functional deficits and to define the role of axonal transport in optic neuritis. If axonal transport defects occur early and persist (as suggested by our preliminary data), this may be a potential therapeutic target.

公共卫生。如果申请获得资助，该描述将按原样成为公共信息。所以，不包括专有/机密信息。请勿超出所提供的空间。我们之前证明弥散张量成像 (DTI) 成功检测轴突和髓磷脂损伤通过降低轴向扩散率（λ║，平行于白质束）和增加径向扩散率（λ，垂直于白质束）在中枢神经系统（CNS）疾病的动物模型中受伤。在最初的计划项目资助期间，我们发现了一些混杂因素，例如炎症和组织损失，导致对 DTI 检测到的轴突病理的误解。因此，我们开发了一种新型扩散基础光谱成像（DBSI）来检测、区分和量化炎症和轴突/髓磷脂损伤（Wang et al. 2011）。在本次 PPG 更新中，体内 DBSI 将用于记录炎症、轴突损伤和炎症的演变。小鼠 EAE 中视神经和脊髓白质束脱髓鞘，与神经系统相关损害。 DBSI 确定的病理学将与免疫组织化学 (IHC) 相关联 EAE 过程以验证 DBSI 损伤标志物。功能障碍与个体相关和/或由 DBSI 和 IHC 确定的轴突病理组合，以确定哪种最好对应于临床损伤。探讨使用 DBSI 作为临床试验终点，FTY720 治疗对功能的影响 EAE 损伤将与 DBSI 确定的视神经和脊髓轴突病理相关小册子并经 IHC 确认。此外，我们将同时使用 DBSI 和广泛报道的锰增强 MRI，同时评估对照组和对照组视神经的顺行轴突传输率。 EAE 小鼠确定轴突运输功能障碍与 DBSI 确定的轴突之间的关系病理学。这将有机会描述视神经炎症或轴突损伤神经功能缺陷的基础，并定义轴突运输在视神经炎中的作用。如果轴突运输缺陷发生得很早并且持续存在（正如我们的初步数据所示），这可能是一个潜在的问题治疗目标。