Viral-induced axonopathy: mechanisms of damage and repair

病毒引起的轴突病：损伤和修复机制

• 批准号: 9014906
• 负责人: Robert S Fujinami
• 金额: $ 36.88万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014906
• 关键词: Axon; Biological Preservation; Cell Therapy; Cell Transplants; Cells; Central Nervous System Infections; Central Nervous System Viral Diseases; Chronic Disease; Clinical; Demyelinating Diseases; Demyelinations; Disease; Disease remission; Employment; Engraftment; Etiology; Exhibits; Genetic; Histologic; Human; Immune; Individual; Infection; Infectious Agent; Infiltration; Inflammation; Inflammatory; Mediating; Methods; Mitochondria; Modality; Modeling; Molecular; Motor; Motor Skills; Multiple Sclerosis; Murine hepatitis virus; Mus; Myelin; Neuraxis; Nitrogen; Oligodendroglia; Operative Surgical Procedures; Outcome; Oxygen; Pathogenesis; Pathology; Role; Running; Spinal Cord; System; T-Lymphocyte; TMEV; Testing; Transplantation; Viral; Virus; Virus Diseases; animal model development; associated symptom; axon injury; axonal degeneration; axonopathy; clinically relevant; design; environmental agent; improved; macrophage; multiple sclerosis patient; nerve stem cell; neurotropic; novel; novel therapeutic intervention; novel therapeutics; public health relevance; remyelination; repaired; research study; response; tool; white matter damage

 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.

 描述（由申请人提供）：多发性硬化（MS）是一种中枢神经系统（CNS）慢性疾病，其特征为多灶性炎症和髓鞘破坏。通常，MS的临床病程延长，持续数十年，伴有急性发作，随后是不同的缓解期。现有证据表明，MS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，开发临床和组织病理学与大多数MS患者相似的动物模型势在必行。脱髓鞘病毒模型是研究疾病发病机制的重要工具。用小鼠肝炎病毒（JHMV）或泰勒氏鼠脑脊髓炎病毒（TMEV）的嗜神经性JHM株持续感染小鼠的特征在于轴突损伤和由炎性T细胞和巨噬细胞介导的持续脱髓鞘，其在临床上和组织学上与人类脱髓鞘疾病MS相似。结合环境因子如病毒被认为是导致MS的原因的事实，MS、JHMV和TMEV系统提供了极好的模型，用于研究可能驱动MS患者脱髓鞘的潜在病理机制以及促进髓鞘再生的新治疗方法。 轴突损伤是MS发病机制中的一个关键特征。在JHMV或TMEV感染CNS后，存在广泛的轴突损伤，其通常先于免疫细胞浸润和脱髓鞘。了解轴突病发生的分子/细胞机制，以应对病毒感染的中枢神经系统将有助于揭示新的方法，以促进轴突保留。沿着这些路线，神经祖细胞（NPC）的就业提供了一个有吸引力的方法来保护轴突和启动髓鞘再生。我们已经确定，脊髓内移植小鼠NPC到JHMV感染的小鼠建立脱髓鞘的结果在改善临床结果与NPC分化成少突胶质细胞，广泛的轴突保留和髓鞘再生。我们的新结果表明，移植的NPC物理参与轴突轴突保存和髓鞘再生。该建议将询问（i）病毒感染CNS后导致轴突病变的分子和细胞机制，以及（ii）与NPC介导的轴突保存和髓鞘再生相关的机制。