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：多型扇贝（MS）的特征是炎症和髓磷脂破坏的多灶，MS经营着持久的临床过程，在严重程度上持续了数十年，并发出了变化。，临床和组织学相似的动物模型与MS患者中观察到的相似是不可能的，无法更好地了解脱叶素的基本病毒模型。（JHMV）或Theiler的鼠脑脊髓炎病毒（TMEV）的特征是轴突损伤和炎症性T细胞和巨噬细胞的脱髓鞘性，这在临床上和人类脱墨色疾病上都相似，该疾病是一种环境药物，例如一种被认为是一种被认为是促进的原因。 MS的机制可能会像新的损害一样驱动MS患者的脱髓鞘轴突和启动均质的方法。（i）导致CNS的轴突病毒感染以及（ii）离子和再生的分子和细胞机制。