Viral-induced axonopathy: mechanisms of damage and repair

病毒引起的轴突病：损伤和修复机制

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：多发性硬化症（MS）是中枢神经系统（CNS）的慢性疾病，其特征是炎症和髓磷脂破坏的多灶区域。通常，MS运行了持续数十年的长期临床过程，并发作加重，随后发生了可变的缓解周期。可用证据表明，MS的原因是多因素的，包括个体的遗传背景以及环境影响，例如病毒感染。为了更好地理解有助于MS的基本病理机制，必须进行临床和组织学病理学与大多数MS患者相似的动物模型的发展。脱髓鞘的病毒模型是研究疾病发病机理的重要工具。小鼠用小鼠肝炎病毒（JHMV）或Theiler的鼠类鼠脑脊髓炎病毒（TMEV）对小鼠的持续感染的特征是轴突损伤和持续的脱髓鞘介导的炎症性T细胞和巨噬细胞所介导的持续脱髓鞘，这在临床上和组织学上都类似于临床上的demyly demeylination to nymy dememelination nymemy demeylination demeylination demeylination demeylination demylelination demylelination。结合以下事实：诸如病毒之类的环境剂被认为是MS的促成原因，JHMV和TMEV系统提供了出色的模型，可以研究既可能驱动MS患者脱髓鞘的潜在病理机制，又可以促进新的治疗方法来促进Remerelination。轴突损伤是MS发病机理中的关键特征。在CNS感染JHMV或TMEV之后，存在广泛的轴突损伤，通常在免疫细胞浸润和脱髓鞘之前。理解轴突病因中枢神经系统的病毒感染而发生的分子/细胞机制将有助于发现新颖的方法来促进轴突保留。沿着这些线路，神经祖细胞（NPC）的使用提供了一种有吸引力的方法来保护轴突并启动透明度。我们已经确定，将小鼠NPC的术内移植具有既定的脱髓鞘性，从而改善了与NPC分化为寡头胶质细胞，广泛的轴突差异和重新呈现的临床结果。我们的新结果表明，植入的NPC会自然接触轴突，从而实现轴突保存和透明度。该建议将询问（i）CNS病毒感染后导致轴突病的分子和细胞机制以及（ii）与NPC介导的轴突保存和remerelination相关的机制。