Attenuating microglial-dependent axonal pathology in EAE

减轻 EAE 中小胶质细胞依赖性轴突病理学

• 批准号: 9889586
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889586
• 关键词: Ablation; Actins; Action Potentials; Anti-Inflammatory Agents; Attenuated; Axon; Brain; Cell Adhesion Molecules; Cells; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive deficits; Consequentialism; Cre-LoxP; Cues; Data; Demyelinating Diseases; Demyelinations; Disease; Ensure; Event; Experimental Autoimmune Encephalomyelitis; Experimental Models; Factor V; Goals; Health system; Immune; Impaired cognition; In Vitro; Inflammatory; Injury; Knock-out; Mediating; Microglia; Modeling; Morphology; Motor; Multiple Sclerosis; Mus; Myelin; Neurologic Dysfunctions; Neurons; Pathologic; Pathology; Play; Process; Production; Protein Isoforms; Role; Sensory; Severity of illness; Site; Structure; Swelling; System; Testing; Veterans; Work; axon injury; base; cell injury; cell type; chronic demyelination; clinically relevant; cytokine; density; disabling disease; effective therapy; functional loss; gray matter; in vivo; migration; motor deficit; mouse model; neurofascin; novel; preservation; repaired; response; restoration; therapeutic target; white matter

Project Summary: Nearly 30,000 US veterans are in the VA system being treated for Multiple Sclerosis (MS), a disabling disease that results in motor, sensory and cognitive dysfunction. There is no cure and treatments have limited efficacy. The overall goal of my lab is to provide a better understanding of the pathologic mechanisms that drive MS in order to develop new and better treatment options. MS is classically described as a demyelinating disorder where myelin loss is accompanied by axonal damage and irreversible neurological dysfunction. The prevail- ing theme is that axonal pathology in MS is consequential of chronic, long term demyelination. Although axon- al pathology clearly results from long term myelin loss, we propose that axonal pathology is also a primary event in MS that occurs early in disease and independent of demyelination. Supportive of this idea, axonal pathology is observed in both normal appearing white and grey matter; MS plaque load does not correlate with axonal loss; and axonal number is reduced in regions lacking myelin loss . In further support that axonal damage occurs independent of myelin loss and at very early stages of disease, we recently demonstrated that axonal pathology is indeed a primary event in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Our findings indicate that the axon initial segment (AIS), the myelin-bare, initial region of the ax- on responsible for action potential initiation and modulation, is specifically targeted by pro-inflammatory, reac- tive microglia in the absence of myelin loss resulting in subsequent AIS disruption. Moreover, we showed that anti-inflammatory treatment not only decreased microglial reactivity and microglia/AIS contact but also result- ed in amelioration of AIS disruption and in AIS restoration. The clinical relevance of these findings is support- ed by our most recent observations indicating that a similar AIS disruption also occurs in MS. Based on our findings, our working hypothesis is that in MS reactive microglia migrate toward injury cues and undergo mor- phologic change resulting in increased contact with the AIS facilitating the targeting of pro-inflammatory fac- tors promoting AIS disruption independent of demyelination. Moreover, we propose that inhibition of microglia response and interaction with the AIS will result in AIS preservation and restoration. Here, we present strong preliminary data that a novel isoform of the cell adhesion molecule neurofascin (Nfasc) mediates the microglia response in the MS model of EAE. Based on our findings and known functions of other Nfasc isoforms, we predict that microglia-specific ablation of Nfasc will 1. inhibit microglial migration, surveillance and cytokine secretion by disrupting actin dynamics and 2. result in structural and functional AIS preservation in EAE.

项目摘要： VA系统中有近30,000名美国退伍军人正在接受多发性硬化症（MS），这是一种致命的疾病 这导致运动，感觉和认知功能障碍。无法治愈，治疗方法有限。 我实验室的总体目标是更好地了解推动MS进入的病理机制 为了开发新的更好的治疗选择。 MS经典被描述为脱髓鞘障碍 髓鞘损失伴随着轴突损伤和不可逆的神经功能障碍。盛行 - Ing主题是MS中的轴突病理是慢性，长期脱髓鞘的结果。虽然轴突 - Al病理显然是由于长期髓磷脂损失而导致的，我们建议轴突病理也是主要的 在疾病早期发生的MS事件，独立于脱髓鞘。支持这个想法，轴突 在正常出现的白质和灰质中都观察到病理。 MS斑块负荷不相关 轴突损失；缺乏髓磷脂损失的地区，轴突数减少了。为了进一步支持轴突 损害与髓鞘丧失无关，在疾病的早期阶段，我们最近证明 轴突病理确实是实验性自身免疫性脑脊髓炎（EAE）的主要事件，小鼠 MS的模型。我们的发现表明，轴突初始段（AIS），髓鞘，轴的初始区域 负责行动潜在的启动和调节，是由促炎性的，重新针对的 在没有髓磷脂损失的情况下，小胶质细胞导致AIS破坏。而且，我们表明 抗炎治疗不仅降低了小胶质细胞反应性和小胶质细胞/AIS接触，而且还会导致 - 在改善AIS中断和AIS恢复方面。这些发现的临床相关性是支持 - 通过我们最近的观察结果表明，MS也发生了类似的AIS中断。基于我们 调查结果，我们的工作假设是，在MS中，反应性小胶质细胞向伤害提示迁移并经历 流向变化导致与AIS接触的增加，促进了促炎性FAC-的靶向 促进AIS中断的TOR独立于脱髓鞘。此外，我们建议抑制小胶质细胞 与AIS的响应和相互作用将导致AIS保存和恢复。在这里，我们呈现强大 细胞粘附分子神经素（NFASC）介导小胶质细胞的新型同工型的初步数据 EAE的MS模型中的响应。根据我们的发现和其他NFASC同工型的已知功能，我们 预测NFASC的小胶质细胞特异性消融将抑制小胶质细胞迁移，监测和细胞因子 通过破坏肌动蛋白动力学和2的分泌。在EAE中导致结构和功能性AIS保存。