Identification and Repair of Novel Axonal Pathology in Demyelinating Disease

脱髓鞘疾病中新型轴突病理学的识别和修复

• 批准号: 8814443
• 负责人: Jeffrey L. Dupree
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8814443
• 关键词: Action Potentials; Affect; Axon; Blurred vision; Cells; Central Nervous System Diseases; Cognitive deficits; Data; Demyelinating Diseases; Demyelinations; Disease; Disease Progression; Event; Experimental Autoimmune Encephalomyelitis; Functional disorder; Impaired cognition; Inflammation; Inflammatory; Limb structure; Location; Mediating; Microglia; Modeling; Molecular; Motor; Multiple Sclerosis; Myelin; Neocortex; Neurons; Numbness; Onset of illness; Pathologic; Pathology; Play; Proteins; Ranvier' s Nodes; Reporting; Resolution; Role; Sensory; Staging; Structure; Teenagers; Testing; Thinking; Time; Veterans; Work; abstracting; axonal degeneration; base; cell injury; cell type; chronic demyelination; design; functional loss; loss of function; motor deficit; neuron loss; novel; public health relevance; repaired; white matter

DESCRIPTION (provided by applicant): Project Summary/Abstract Multiple sclerosis is a devastating disease of the central nervous system that affects thousands of US veterans. MS frequently initially presents as temporary tingling or numbness in extremities or blurred vision. However, with time these "events" result in an accumulation of deficits leading to irreversible motor, sensory and cognitive dysfunction. Presently, there are no cures for MS. Treatment are available but their efficacy is highly variable and loss of motor function appears irreversible. Although classically described as a demyelinating disease, more recent studies have shown that axonal pathology is prevalent in MS and that this axonal pathology may be responsible for the irreversible loss of function associated with the disease. Here, we present strong preliminary data that challenge this view of MS. We show that a specific domain along the axon, known as the axon initial segment is structurally disrupted independent of demyelination indicating that axonal pathology in MS is a primary event and not merely consequential to demyelination. Structural disruption of the axon initial segment is functional devastating to the CNS since it is within the initial segment where i is decided whether an action potential will be generated. If our hypothesis is current, then disease onset does not parallel demyelinating episodes but occurs significantly earlier. Although our findings could revolutionize the view of MS onset, more importantly, we present strong preliminary data that disruption of the axon initial segment is reversible. Presently, we provide morphologic data suggesting reversibility. In this proposal we will test functional reversibility. Together, the studies outlined in this proposal are designed to challenge the current thinking of MS onset and the pathologic mechanisms that mediate the earliest stages of the disease. Moreover, we will further investigate the possibility that dysfunction that results form MS is reversible.

描述（由申请人提供）： 项目摘要/摘要 多发性硬化症是一种破坏性的中枢神经系统疾病，影响着数千名美国退伍军人。多发性硬化症最初常常表现为四肢暂时刺痛或麻木或视力模糊。然而，随着时间的推移，这些“事件”会导致缺陷累积，导致不可逆转的运动、感觉和认知功能障碍。目前，多发性硬化症尚无治愈方法。治疗是可用的，但其疗效差异很大 并且运动功能的丧失似乎是不可逆转的。尽管传统上被描述为脱髓鞘疾病，但最近的研究表明，轴突病理学在多发性硬化症中普遍存在，并且这种轴突病理学可能是与该疾病相关的不可逆功能丧失的原因。在这里，我们提供了强有力的初步数据来挑战 MS 的这一观点。我们发现，沿轴突的一个特定区域（称为轴突初始段）在结构上受到破坏，与脱髓鞘无关，表明多发性硬化症中的轴突病理是主要事件，而不仅仅是脱髓鞘的结果。轴突初始段的结构破坏对中枢神经系统的功能具有破坏性，因为它是在初始段内决定是否会产生动作电位。如果我们的假设是正确的，那么疾病的发作并不与脱髓鞘事件同时发生，而是发生得更早。尽管我们的发现可能会彻底改变多发性硬化症发病的观点，但更重要的是，我们提供了强有力的初步数据，表明轴突初始段的破坏是可逆的。目前，我们提供了表明可逆性的形态学数据。在此提案中，我们将测试功能可逆性。总之，本提案中概述的研究旨在挑战当前对多发性硬化症发病的看法以及介导该疾病最早阶段的病理机制。此外，我们将进一步研究多发性硬化症导致的功能障碍是否可逆。