The Mechanism of Gray Matter Atrophy in Experimental Autoimmune Encephalomyelitis

项目总结/摘要 多发性硬化症（MS）是一种公认的中枢神经系统自身免疫性疾病 其特征在于炎症、脱髓鞘和灰质（GM）萎缩。长期以来，MS一直被视为 尽管如此，GM参与是白色疾病的重要组成部分， 与临床残疾有直接关系。事实上，最常见的残疾之一，认知障碍 萎缩比T2病变体积更好地解释了损伤，这似乎在两种情况下都是正确的 复发缓解型MS（RRMS）和良性MS，提示认知障碍的无声进展 独立于MS临床过程。然而，目前的免疫调节治疗仅具有适度的效果。 成功减少MS患者GM萎缩和残疾累积。因此， 在开发MS的神经保护治疗方面取得进展-了解神经机制 导致GM萎缩，以便成功地靶向神经保护治疗。 据报道，在最常用的MS小鼠模型，实验性自身免疫性 脑脊髓炎（EAE），脊髓病变中的轴突损伤至少部分是由反应性 由活化的小胶质细胞和巨噬细胞产生的氧物质（ROS）和活性氮物质（RNS 在病变部位。线粒体对氧化损伤高度敏感，不仅在脊髓中， 在大脑皮层中。我们已经观察到EAE小鼠大脑皮质中活化的小胶质细胞， 这表明氧化应激也可能是大脑皮层中突触和神经元损失的原因。 因此，我们假设氧化应激导致大脑皮层线粒体功能障碍， 由于线粒体功能障碍而导致的生物能量不足反过来导致突触和神经元损失 在大脑皮层中。我们将通过调节神经元的中和能力来验证这一假设。 超氧化物，氧化应激的主要成分。我们还将补充神经元生物能量学， 疾病，以更好地了解突触丢失和GM萎缩的基础过程。 这项工作将为氧化应激， 线粒体功能障碍和皮质GM萎缩，这些可能有一天会被用于治疗。

Project Summary/Abstract Multiple Sclerosis (MS) is a putative autoimmune disease of the central nervous system (CNS) characterized by inflammation, demyelination, and gray matter (GM) atrophy. MS has long been regarded as a disease of white matter (WM), nevertheless, GM involvement is an important component of the disease and has a direct relationship to clinical disability. In fact, one of the most commonly occurring disabilities, cognitive impairment, was better explained by atrophy than by T2 lesion volume and this appears to be true in both relapsing remitting MS (RRMS) and benign MS, suggesting a silent progression of cognitive impairment independent of MS clinical course. However, current immunomodulatory treatments have only had modest success at reducing GM atrophy and disability accumulation in patients with MS. Thus, there is a critical barrier to progress in developing neuroprotective treatments for MS – an understanding of the neuronal mechanisms that lead to GM atrophy in order to successfully target neuroprotective therapeutics. It has been reported in the most commonly used mouse model of MS, experimental autoimmune encephalomyelitis (EAE), that axonal damage in spinal cord lesions is caused at least in part by reactive oxygen species (ROS) and reactive nitrogen species (RNS) produced by activated microglia and macrophages at the site of lesions. Mitochondria are highly susceptible to oxidative injury, not only in the spinal cord, but also in the cerebral cortex. We have observed activated microglia in the cerebral cortices of mice with EAE, suggesting that oxidative stress may also be responsible for synaptic and neuronal loss in the cerebral cortex. Thus, we hypothesize that oxidative stress causes mitochondrial dysfunction in the cerebral cortex and that bioenergetic insufficiency due to mitochondrial dysfunction is in turn responsible for synaptic and neuronal loss in the cerebral cortex. We will test this hypothesis by modulating the capacity of neurons to neutralize superoxide, a major component of oxidative stress. We will also supplement neuronal bioenergetics during disease to better understand the processes that underlie synaptic loss and GM atrophy. The proposed work will provide important new insights into the relationship between oxidative stress, mitochondrial dysfunction and cortical GM atrophy that could someday be harnessed for therapeutic benefit.