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; 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（由申请人提供）：尚不清楚慢性斑块中神经元再生和再生的原因是MS患者中最普遍的病变。该项目将检验以下假设：急性MS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。 ECM硫酸乙酰肝素蛋白聚糖（HSPG）的病理生理和MS中涉及神经元出生的信号分子的病理生物生理。在不同的MS病变阶段，对照患者中枢神经系统样本以及在神经病理学上不同的小鼠MS模型中，ECM HSPGS和Agrin的碎片化，细胞和地形定位程度可以分析以确定与病变进展和特定损伤模式的关系。酶促降解的ECM HSPG对神经突生长的影响将直接在体外模型中进行评估。 ephrins（Eph）和ephrin受体（EPH）的表达是在CNS的正常和灰质患者中，将在病变中分析具有抑制性和刺激作用的神经元信号分子家族和CNS发育中CNS发育中的抑制作用和刺激作用。还将评估分解代谢的ECM蛋白聚糖对神经突生长中EPH/EPH表达的影响。从这些原位和体外研究中，将阐明ECM蛋白聚糖分解和EPH/EPH改变对神经元再生失败的贡献。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，并将指向针对CNS ECM和EPH/EPH的新的特定疗法。此外，它们对于理解基于干细胞的MS病变疗法的结果很重要，这些疗法需要概括取决于CNS ECM和EPH/EPH信号传导的发育过程。