Identification and Repair of Novel Axonal Pathology in Demyelinating Disease

描述（由申请人提供）： 多发性硬化症是一种中枢神经系统的毁灭性疾病，影响着成千上万的美国退伍军人。多发性硬化症通常最初表现为四肢暂时性刺痛或麻木或视力模糊。然而，随着时间的推移，这些“事件”导致缺陷的积累，导致不可逆的运动、感觉和认知功能障碍。目前，没有治愈MS的方法。治疗是可用的，但其疗效是高度可变的 运动功能的丧失似乎是不可逆转的。虽然经典地描述为脱髓鞘疾病，但最近的研究表明，轴突病理在MS中普遍存在，并且这种轴突病理可能是与疾病相关的不可逆功能丧失的原因。在这里，我们提出了强有力的初步数据，挑战这一观点的MS。我们表明，一个特定的域沿沿着的轴突，称为轴突的初始段结构中断独立的脱髓鞘，表明在MS的轴突病理是一个主要的事件，而不仅仅是相应的脱髓鞘。轴突起始段的结构破坏对CNS的功能是破坏性的，因为它是在起始段内，其中i决定是否将产生动作电位。如果我们的假设是当前的，那么疾病的发作不平行脱髓鞘发作，但发生显着更早。虽然我们的研究结果可能会彻底改变MS发病的观点，但更重要的是，我们提出了强有力的初步数据，即轴突起始段的破坏是可逆的。目前，我们提供的形态学数据表明可逆性。在本提案中，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目前对MS发病的看法以及介导疾病最早阶段的病理机制。此外，我们将进一步研究MS导致的功能障碍是可逆的可能性。

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.