Axonal degeneration can trigger demyelinating disease

轴突变性可引发脱髓鞘疾病

• 批准号: 7588706
• 负责人: IKUO TSUNODA
• 金额: $ 14.96万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588706
• 关键词: Adoptive Transfer; Allergic; Animal Model; Antigen Presentation; Area; Autoimmune Process; Automobile Driving; Axon; Axonal Transport; Biological Preservation; Brain; Cell Adhesion Molecules; Cells; Cessation of life; Chronic Phase; Data; Demyelinating Diseases; Demyelinations; Disease; Encephalomyelitis; Equilibrium; Etiology; Experimental Autoimmune Encephalomyelitis; Figs - dietary; Goals; Hand; Immune response; Inbred C57BL Mice; Infection; Inflammation; Inflammatory; Injury; Lead; Lesion; Location; Mediating; Modeling; Multiple Sclerosis; Mus; Mutant Strains Mice; Myelin; Myelin Sheath; Myelitis; Neural Conduction; Neuraxis; Neurologic; Neurons; Oligodendroglia; Pathology; Pathway interactions; Pattern; Phase; Play; Process; Public Health; Recruitment Activity; Role; Severities; Site; Study Section; T-Lymphocyte; TMEV; Viral; Virus; Virus Diseases; Wallerian Degeneration; Wild Type Mouse; axonal flow; chemokine; cytokine; disorder subtype; mutant; neuroprotection; neurotropic virus; response

DESCRIPTION (provided by applicant): A neuron transmits information via its process, the axon. The axon is wrapped by the myelin sheath, which is required for efficient nerve conduction. Although myelin destruction (demyelination) is a cardinal feature in multiple sclerosis (MS), axonal damage also occurs. Since the primary target in MS is myelin or myelin- forming cells, the oligodendrocytes, axonal injury is believed to occur secondarily after myelin and oligodendrocytes are damaged. In this Outside-In destruction model, lesions develop from the outside (myelin) to the inside (axon). However, in an animal model for MS, Theiler's murine encephalomyelitis virus (TMEV) infection, axonal damage precedes demyelination. In TMEV infection, the distribution of axonal damage during the early phase corresponds to regions where subsequent demyelination occurs during the chronic phase. This suggests that initial axonal damage may alter the local microenvironment, resulting in the recruitment of inflammatory cells to the site of axonal degeneration, which in turn leads to demyelination. In this scenario, lesions can develop from the inside (axon) to the outside (myelin) (Inside-Out model). While it is not known why distinct areas of the brain are involved in MS, preceding axonal damage might play an important role in targeting inflammatory cells to particular sites in the brain. First, we will determine whether experimentally induced axonal damage alters the distribution of inflammatory demyelinating lesions in a viral model for MS, TMEV infection, and an autoimmune model for MS, experimental autoimmune encephalomyelitis (EAE), by modulation of expression of adhesion molecules, cytokines and chemokines. Second, we will compare wild- type mice with genetically mutant mice (C57BL/WldS mice) that lack (or delay) axonal degeneration to investigate roles of axonal damage in TMEV infection and EAE. Interactions between axons and myelin/oligodendrocytes are important for oligodendrocyte and axon survival. Thus, axonal injury itself can induce oligodendrocyte death, leading to the spread of demyelination. Since the mutant mice lack axonal degeneration, the extent of demyelination will be smaller in mutant mice than in wild-type mice. On the other hand, axonal degeneration might play a beneficial role for hosts in virus infection. Some viruses, including TMEV, can spread in the brain using axons. In this case, axonal degeneration can inhibit axonal transport of viruses and suppress virus dissemination in the brain. Since axonal injury in MS contributes to permanent neurological deficits, protection from or treatment of such injury would ameliorate the devastating effects of MS. A spectrum of infections associated with MS may induce axonal damage first, leading to demyelination second (Inside-Out model). Most likely, there is a balance of the Outside-In and Inside-Out processes depending on the model or disease subtype of MS. The Inside-Out model may initially drive the disease, leading to myelin antigen presentation in the brain and stimulation of Outside-In responses, which result in further damage to axons, setting up a cycle of pathology involving both pathways. PUBLIC HEALTH RELEVANCE: Axonal damage in multiple sclerosis (MS) contributes to permanent neurological deficits. Therefore, it is important to understand the mechanisms of axonal damage. This project seeks to elucidate a potential beneficial versus detrimental role of axonal degeneration and its relationship to inflammation and demyelination, using viral and autoimmune models for MS.

描述（由申请人提供）：神经元通过其过程轴突传输信息。轴突被髓鞘包裹，这是有效的神经传导所必需的。尽管髓磷脂破坏（脱髓鞘）是多发性硬化症（MS）的基本特征，但也会发生轴突损伤。由于MS中的主要靶标是髓磷脂或髓磷脂细胞，因此少突胶质细胞，轴突损伤被认为是在髓磷脂和少突胶质细胞受损之后其次发生的。在这种外部破坏模型中，病变​​从外部（髓磷脂）发展到内部（轴突）。但是，在MS动物模型中，Theiler的鼠脑脊髓炎病毒（TMEV）感染，轴突损伤先于脱髓鞘。在TMEV感染中，早期轴突损伤的分布对应于随后在慢性期发生随后发生脱髓鞘的区域。这表明最初的轴突损伤可能会改变局部微环境，从而导致炎症细胞募集到轴突变性的部位，从而导致脱髓鞘。在这种情况下，病变可以从内部（轴突）到外部（髓磷脂）（内而外模型）发展。虽然尚不清楚为什么大脑的不同区域参与MS，但轴突损伤可能在靶向炎症细胞到大脑的特定部位方面起重要作用。首先，我们将确定通过通过调节MS，TMEV感染的病毒模型中的炎症性脱髓鞘病变的分布，用于MS，MS的自身免疫模型，实验性自身免疫性脑脊髓炎（EAE）的分布，通过调节粘附分子的表达，实验性自身免疫性脑脊髓炎（EAE）。其次，我们将缺乏（或延迟）轴突变性的遗传突变小鼠（C57BL/WLDS小鼠）进行比较，以研究轴突损伤在TMEV感染和EAE中的作用。轴突和髓磷脂/少突胶质细胞之间的相互作用对于少突胶质细胞和轴突存活至关重要。因此，轴突损伤本身可以诱导少突胶质细胞死亡，从而导致脱髓鞘的扩散。由于突变小鼠缺乏轴突变性，突变小鼠中脱髓鞘的程度将比野生型小鼠小。另一方面，轴突变性可能对宿主在病毒感染中起有益作用。一些病毒，包括TMEV，可以使用轴突在大脑中扩散。在这种情况下，轴突变性可以抑制病毒的轴突运输并抑制大脑中的病毒传播。由于MS中的轴突损伤导致永久性神经缺陷，因此免受此类损伤的保护或治疗将改善MS的破坏性作用。与MS相关的一系列感染可能首先会诱导轴突损伤，从而导致第二（内部模型）脱髓鞘。最有可能的是，根据MS的模型或疾病亚型，外部和内外的过程平衡。内而外的模型最初可能会驱动疾病，从而导致大脑中的髓磷脂抗原表现并刺激外部反应，从而进一步损害轴突，从而建立了涉及这两种途径的病理循环。公共卫生相关性：多发性硬化症（MS）的轴突损伤导致永久性神经缺陷。因此，重要的是要了解轴突损伤的机制。该项目旨在利用MS的病毒和自身免疫模型来阐明轴突变性的潜在有益与有害作用及其与炎症和脱髓鞘的关系。