The Mechanism of Gray Matter Atrophy in Experimental Autoimmune Encephalomyelitis

实验性自身免疫性脑脊髓炎灰质萎缩的机制

基本信息

批准号：
10196697
负责人：
Allan James MacKenzie-Graham
金额：
$ 42.9万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10196697
关键词：
Acrylamides Affect Animal Model Atlases Atrophic Benign Bioenergetics CNS autoimmune disease Cerebral cortex Chronic Clinical Demyelinations Dendritic Spines Disease Exhibits Experimental Autoimmune Encephalomyelitis Hybrids Hydrogels Image Impaired cognition Inflammation Knock-out Lead Lesion Link Lipids Magnetic Resonance Imaging Mediating Microglia Mitochondria Multiple Sclerosis Mus Mutant Strains Mice Mutation Neurons Nicotinamide adenine dinucleotide Oxidative Stress Process Production Public Health Reactive Nitrogen Species Reactive Oxygen Species Relapsing-Remitting Multiple Sclerosis Reporting Role Site Spinal Cord Spinal Cord Lesions Superoxides Synapses Testing Therapeutic Tissues Transgenic Organisms Wallerian Degeneration White Matter Disease Work axon injury axonal degeneration base cerebral atrophy disability gray matter human disease immunomodulatory therapies in vivo insight macrophage mitochondrial dysfunction morphometry mouse model multiple sclerosis patient multiple sclerosis treatment neuron loss overexpression oxidative damage preservation prevent success superoxide dismutase 1

项目摘要

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.

项目概要/摘要多发性硬化症 (MS) 是一种假定的中枢神经系统 (CNS) 自身免疫性疾病以炎症、脱髓鞘和灰质（GM）萎缩为特征的多发性硬化症长期以来被认为是一种疾病。然而，白质疾病（WM）的 GM 参与是该疾病的重要组成部分，并且事实上，认知障碍是最常见的障碍之一。萎缩比 T2 病变体积更好地解释了损伤，这在两者中似乎都是如此复发缓解型多发性硬化症 (RRMS) 和良性多发性硬化症，表明认知障碍的无声进展然而，目前的免疫调节治疗效果有限。成功减少多发性硬化症患者的 GM 萎缩和残疾积累因此，存在一个关键障碍。促进多发性硬化症神经保护治疗的发展——了解神经机制导致 GM 萎缩，以便成功地针对神经保护治疗。据报道，最常用的多发性硬化症小鼠模型，实验性自身免疫脑脊髓炎（EAE），脊髓病变中的轴突损伤至少部分是由反应性引起的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) 病变部位的线粒体非常容易受到氧化损伤，不仅在脊髓中，而且在脊髓中也是如此。我们在患有 EAE 的小鼠的大脑皮层中观察到了小胶质细胞，表明氧化应激也可能是大脑皮层突触和神经元损失的原因。因此，我们认为氧化应激会导致大脑皮层线粒体功能障碍，并且线粒体功能障碍导致的生物能量不足反过来又导致突触和神经元损失我们将通过调节神经元的中和能力来检验这一假设。超氧化物，氧化应激的主要成分，我们还将在期间补充神经元生物能量。疾病，以更好地了解突触损失和 GM 萎缩的过程。拟议的工作将为氧化应激、线粒体功能障碍和皮质 GM 萎缩有朝一日可以用于治疗效果。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Estrogen receptor beta in astrocytes modulates cognitive function in mid-age female mice.

星形胶质细胞中的雌激素受体β调节中年雌性小鼠的认知功能。

DOI：
10.1038/s41467-023-41723-7
发表时间：
2023-09-28
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Itoh, Noriko;Itoh, Yuichiro;Meyer, Cassandra E.;Suen, Timothy Takazo;Cortez-Delgado, Diego;Lomeli, Michelle Rivera;Wendin, Sophia;Somepalli, Sri Sanjana;Golden, Lisa C.;MacKenzie-Graham, Allan;Voskuhl, Rhonda R.
通讯作者：
Voskuhl, Rhonda R.