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: 6909891
• 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/6909891
• 关键词: agrin; animal tissue; axon; biological signal transduction; biopsy; central nervous system; clinical research; ephrins; 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(申请人提供)：慢性斑块中神经元再生和再生失败的原因尚不清楚，慢性斑块是MS患者中最常见的病变。该项目将检验一种假设，即发生在急性MS病变中的细胞外基质(ECM)分子破坏，有助于慢性病变中受损的轴突再生。将研究细胞外基质硫酸乙酰肝素蛋白多糖(HSPG)改变的病理生理学，以及参与MS神经元突起生长的信号分子。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 HSPGs Perlecan和agrin的碎裂程度以及细胞和地形图定位，以确定与病变进展和特定损伤模式的关系。酶降解的ECM HSPGs对轴突生长的影响将在体外模型中直接评估。肾上腺素(Eph)和受体(Eph)是一类在中枢神经系统发育中对轴突生长和寻路具有抑制和刺激作用的神经信号分子家族，将分析MS患者皮损、正常外观的白质和灰质、对照CNS组织和小鼠MS模型中的表达变化，以确定表达变化与特定神经病理特征的关系。分解的ECM蛋白多糖对轴突生长中Eph/Eph表达的影响也将被评估。通过这些联合的原位和体外研究，ECM蛋白多糖的降解和Eph/Eph的改变在神经元再生失败中的作用将被阐明。所获得的信息将是理解导致MS病变内源性修复失败的细胞和分子机制的关键，并将指向针对CNS ECM和Eph/Eph的新的特定治疗方法。此外，它们对于理解基于干细胞的MS损伤治疗的结果将是重要的，这些损伤需要回顾依赖于CNS ECM和Eph/Eph信号的发育过程。