Failure of Axon Repair in Chronic MS Lesions

慢性多发性硬化症病变中轴突修复失败

• 批准号: 6667921
• 负责人: RAYMOND A SOBEL
• 金额: $ 15.44万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6667921
• 关键词: agrin; animal tissue; axon; biological signal transduction; biopsy; central nervous system; clinical research; extracellular matrix; heparan sulfate; human tissue; immunocytochemistry; immunoelectron microscopy; laboratory mouse; membrane proteins; multiple sclerosis; nervous system regeneration; neuronal guidance; neurons; postmortem; proteoglycan; receptor; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): The reasons for failure of neuron regeneration and regrowth in chronic plaques, the most prevalent lesions in MS patients, are not understood. This project will test the hypothesis that the extracellular matrix (ECM) molecule breakdown, which occurs in acute MS lesions, contributes to impaired axonal regrowth in chronic lesions. The pathophysiology of ECM heparan sulfate proteoglycan (HSPG) alterations and of signaling molecules involved in neuronal outgrowth in MS will be investigated. The extent of fragmentation and cellular and topographic localization of the ECM HSPGs perlecan and agrin in different MS lesion stages, in control patient CNS samples and in neuropathologically distinct mouse MS models wilt be analyzed to determine relationships to lesion progression and specific injury patterns. The effects of enzymatically degraded ECM HSPGs on neurite outgrowth will be assessed directly in an in vitro model. The expression of ephrins (eph) and ephrin receptors (Eph), a family of neuron signaling molecules with both inhibitory and stimulatory roles in axonal growth and path finding in CNS development, will be analyzed in lesions, normal-appearing white and gray matter in MS patients, in control CNS tissues and in mouse MS models to determine relationships of expression alterations to specific neuropathologic features. Effects of catabolized ECM proteoglycans on eph/Eph expression in neurite outgrowth will also be assessed. From these combined in situ and in vitro studies, the contributions of ECM proteoglycan breakdown and eph/Eph alterations to the failure of neuron regrowth will be elucidated. The information obtained will be essential for understanding cellular and molecular mechanisms that result in the failure of endogenous repair in MS lesions and will point to new, specific therapies targeting the CNS ECM and eph/Eph. Moreover, they will be important for understanding results of stem cell-based therapies of MS lesions which require recapitulation of developmental processes that are dependent on the CNS ECM and eph/Eph signaling.

描述（由申请人提供）：慢性斑块（多发性硬化症患者中最常见的病变）神经元再生和再生长失败的原因尚不清楚。该项目将检验以下假设：急性多发性硬化症病变中发生的细胞外基质 (ECM) 分子分解会导致慢性病变中轴突再生受损。我们将研究 ECM 硫酸乙酰肝素蛋白多糖 (HSPG) 改变以及参与 MS 神经元生长的信号分子的病理生理学。将分析不同 MS 病变阶段、对照患者 CNS 样本和神经病理学不同的小鼠 MS 模型中 ECM HSPG 基底蛋白聚糖和聚集蛋白的断裂程度以及细胞和地形定位，以确定与病变进展和特定损伤模式的关系。酶降解的 ECM HSPG 对神经突生长的影响将在体外模型中直接评估。肝配蛋白 (eph) 和肝配蛋白受体 (Eph) 是一个神经元信号分子家族，在轴突生长和中枢神经系统发育路径寻找中具有抑制和刺激作用，将在多发性硬化症患者的病变、正常白质和灰质、对照中枢神经系统组织和小鼠多发性硬化症模型中分析肝配蛋白 (eph) 和肝配蛋白受体 (Eph) 的表达，以确定表达变化与特定神经病理特征的关系。还将评估分解代谢的 ECM 蛋白多糖对神经突生长中 eph/Eph 表达的影响。通过这些原位和体外联合研究，将阐明 ECM 蛋白聚糖分解和 eph/Eph 改变对神经元再生失败的影响。获得的信息对于理解导致 MS 病变内源性修复失败的细胞和分子机制至关重要，并将指出针对 CNS ECM 和 eph/Eph 的新的特异性疗法。此外，它们对于理解基于干细胞的多发性硬化症病变治疗的结果非常重要，这些治疗需要重演依赖于 CNS ECM 和 eph/Eph 信号传导的发育过程。