Viral-induced axonopathy: mechanisms of damage and repair

 描述(申请人提供)：多发性硬化症(MS)是一种慢性中枢神经系统(CNS)疾病，以多灶性炎症和髓鞘破坏为特征。通常情况下，多发性硬化症的临床病程漫长，持续数十年，伴随着不同的病情加重和不同的缓解期。现有证据表明，多发性硬化症的病因是多因素的，包括个体的遗传背景以及环境影响，例如病毒感染。为了更好地了解MS的潜在病理机制，临床和组织病理学与大多数MS患者相似的动物模型的建立势在必行。脱髓鞘的病毒模型是研究疾病发病机制的重要工具。小鼠持续感染嗜神经性JHM株小鼠肝炎病毒(JHMV)或泰勒氏小鼠脑脊髓炎病毒(TMEV)的特征是由炎症T细胞和巨噬细胞介导的轴突损伤和持续的脱髓鞘，在临床和组织学上与人类脱髓鞘疾病相似，再加上环境因素(如病毒)被认为是多发性硬化症的诱因，JHMV和TMEV系统提供了极好的模型，可以研究可能导致多发性硬化症患者脱髓鞘的潜在病理机制以及促进再髓鞘形成的新颖治疗方法。轴突损伤是MS发病机制中的一个重要特征。无论是JHMV还是TMEV感染中枢神经系统后，都会出现广泛的轴突损伤，通常先于免疫细胞的浸润和脱髓鞘。了解中枢神经系统病毒感染后发生轴索病变的分子/细胞机制将有助于发现促进轴突保留的新方法。沿着这些思路，使用神经前体细胞(NPC)提供了一种诱人的方法，既可以保护轴突，又可以启动重新髓鞘形成。我们已经确定，将小鼠神经干细胞移植到已确定脱髓鞘的JHMV感染小鼠的脊髓内，可以改善与神经干细胞分化为少突胶质细胞、广泛的轴突保留和重新髓鞘形成相关的临床结果。我们的新结果表明，移植的NPC在物理上与轴突接触，导致轴突保留和重新髓鞘形成。这项建议将询问(I)病毒感染中枢神经系统后导致轴索病变的分子和细胞机制，以及(Ii)与NPC介导的轴突保存和重新髓鞘形成相关的机制。

 DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by multifocal regions of inflammation and myelin destruction. Typically, MS runs a protracted clinical course lasting over several decades with episodes of exacerbation followed by variable periods of remission. Available evidence indicates that the cause of MS is multifactorial and includes the genetic background of the individual as well as environmental influences, e.g. viral infection. The development of animal models in which the clinical and histologic pathology is similar to that observed in the majority of MS patients is imperative in order to attempt to better understand the underlying pathological mechanisms contributing to MS. Viral models of demyelination are important tools for studying the pathogenesis of disease. Persistent infection of mice with the neurotropic JHM strain of mouse hepatitis virus (JHMV) or Theiler's murine encephalomyelitis virus (TMEV) is characterized by axonal damage and ongoing demyelination mediated by inflammatory T cells and macrophages, which is similar both clinically and histologically to the human demyelinating disease MS. Combined with the fact that an environmental agent such as a virus is considered to be a contributing cause of MS, the JHMV and TMEV systems offer excellent models in which to study both the underlying pathological mechanisms that may drive demyelination in MS patients as well as novel therapeutic methods for promoting remyelination. Axonal damage is a key feature in the pathogenesis of MS. Following CNS infection with either JHMV or TMEV, there is extensive axonal damage that often precedes immune cell infiltration and demyelination. Understanding the molecular/cellular mechanisms by which axonopathy occurs in response to viral infection of the CNS will aid in uncovering novel ways to promote axonal sparing. Along these lines, employment of neural progenitor cells (NPCs) offers an attractive approach to both protect axons and initiate remyelination. We have determined that intraspinal transplantation of mouse NPCs into JHMV-infected mice with established demyelination results in improved clinical outcome associated with the differentiation of NPCs into oligodendroglia, extensive axonal sparing and remyelination. Our new results demonstrate that engrafted NPCs physically engage axons resulting in axonal preservation and remyelination. This proposal will interrogate (i) the molecular and cellular mechanisms resulting in axonopathy following viral infection of the CNS and (ii) mechanisms associated with NPC-mediated axonal preservation and remyelination.