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：
9243327
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/9243327
关键词：
Axon Biological Preservation Cell Differentiation process Cell Therapy Cell Transplants Cells Central Nervous System Diseases 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 Mouse Strains Multiple Sclerosis Murine hepatitis virus Mus Myelin Neuraxis Nitrogen Oligodendroglia Operative Surgical Procedures Outcome Oxygen Pathogenesis Pathologic 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 experimental study improved macrophage multiple sclerosis patient nerve stem cell neurotropic novel novel therapeutic intervention novel therapeutics public health relevance remyelination repaired 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（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统（CNS）的慢性疾病，其特征是多灶性区域炎症和髓磷脂破坏，通常，多发性硬化症的临床病程持续数十年，并伴有发作性加重。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，例如临床上病毒感染的影响。为了更好地了解多发性硬化症的潜在病理机制，必须采用与大多数多发性硬化症患者观察到的组织学病理学相似的脱髓鞘病毒模型，这是研究多发性硬化症小鼠持续感染发病机制的重要工具。小鼠肝炎病毒 (JHMV) 或泰勒氏鼠脑脊髓炎病毒 (TMEV) 的神经性 JHM 株的特征是炎症 T 细胞介导的轴突损伤和持续脱髓鞘，巨噬细胞在临床和组织学上与人类脱髓鞘疾病 MS 相似，再加上病毒等环境因素被认为是 MS 的致病因素，JHMV 和 TMEV 系统提供了极好的研究模型。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髓鞘再生的新治疗方法是中枢神经系统感染 JHMV 后的一个关键特征。或 TMEV，轴突损伤通常发生在免疫细胞浸润和脱髓鞘之前，了解中枢神经系统广泛病毒感染发生轴突病变的分子/细胞机制将有助于发现促进轴突保护的新方法。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和启动髓鞘再生。已确定脱髓鞘的 JHMV 感染小鼠可改善与 NPC 分化为少突神经胶质细胞、广泛的轴突保留和髓鞘再生相关的临床结果。 ) 中枢神经系统病毒感染后导致轴突病变的分子和细胞机制，以及 (ii) 与 NPC 介导的轴突保存相关的机制和髓鞘再生。