Failure of Axon Repair in Chronic MS Lesions

描述（由申请人提供）：MS患者中最常见的病变慢性斑块神经元再生和再生失败的原因尚不清楚。该项目将测试急性MS病变中发生的细胞外基质（ECM）分子分解导致慢性病变轴突再生受损的假设。我们将研究多发性硬化症中ECM中硫酸肝素蛋白聚糖（HSPG）的改变和参与神经元生长的信号分子的病理生理。将分析不同MS病变阶段、对照患者中枢神经系统样本和神经病理学不同的小鼠MS模型中ECM HSPGs、perlecan和agrin的碎片化程度、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 HSPGs对神经突生长的影响将在体外模型中直接评估。ephrin （eph）和ephrin受体（eph）是一个神经元信号分子家族，在中枢神经系统发育的轴突生长和寻径过程中具有抑制和刺激作用，将在MS患者的病变、正常的白质和灰质、对照中枢神经系统组织和小鼠MS模型中分析表达改变与特定神经病理特征的关系。分解代谢的ECM蛋白聚糖对神经突生长中eph/ eph表达的影响也将被评估。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，并将指出针对CNS ECM和eph/ eph的新的特异性治疗方法。此外，它们对于理解MS病变的干细胞治疗结果也很重要，因为MS病变需要重现依赖于CNS ECM和eph/ eph信号传导的发育过程。

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.