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: 10620206
• 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/10620206
• 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; 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; LoxP-flanked allele; 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; Traction; Veterans; Work; axon injury; 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.

项目概要： 近 30,000 名美国退伍军人在 VA 系统中接受多发性硬化症 (MS) 的治疗，这是一种致残疾病 导致运动、感觉和认知功能障碍。目前尚无治愈方法，且治疗效果有限。 我实验室的总体目标是更好地了解驱动多发性硬化症的病理机制 以开发新的、更好的治疗方案。 MS 通常被描述为一种脱髓鞘疾病 髓鞘质损失伴随着轴突损伤和不可逆的神经功能障碍。占上风的是—— 主题是多发性硬化症的轴突病理是慢性、长期脱髓鞘的结果。虽然轴突- 尽管病理学显然是由长期髓磷脂丢失引起的，但我们认为轴突病理学也是主要的原因。 MS 中发生在疾病早期且与脱髓鞘无关的事件。支持这个观点，轴突 在正常的白质和灰质中均观察到病理现象； MS 菌斑负荷不相关 伴有轴突损失；在没有髓磷脂损失的区域，轴突数量减少。进一步支持轴突 损伤的发生与髓磷脂损失无关，并且发生在疾病的非常早期阶段，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 模型。我们的研究结果表明，轴突初始段（AIS），即裸露的髓磷脂，轴突的初始区域 负责动作电位的启动和调节，特别针对促炎、反应 在没有髓鞘质丢失的情况下，小胶质细胞会被激活，从而导致随后的 AIS 破坏。此外，我们还表明 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，而且还导致 - 旨在改善 AIS 中断和恢复 AIS。这些发现的临床相关性支持- 我们最近的观察表明，类似的 AIS 破坏也发生在 MS 中。基于我们的 研究结果表明，我们的工作假设是，在多发性硬化症中，反应性小胶质细胞会向损伤线索迁移并经历更多的过程。 病理变化导致与 AIS 的接触增加，促进促炎因子的靶向 促进 AIS 破坏的因素与脱髓鞘无关。此外，我们建议抑制小胶质细胞 与 AIS 的响应和交互将导致 AIS 的保存和恢复。在这里，我们向您展示强大的 初步数据表明细胞粘附分子神经成束蛋白 (Nfasc) 的新型亚型介导小胶质细胞 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 1. 抑制小胶质细胞迁移、监视和细胞因子 2. 通过破坏肌动蛋白动力学进行分泌，导致 EAE 中 AIS 的结构和功能得以保留。

项目成果

Chronic peripheral nerve compression disrupts paranodal axoglial junctions.

慢性周围神经受压会破坏节旁轴胶质连接。

• 发表时间: 2017
• 影响因子: 3.4
• 作者: Otani, Yoshinori;Yermakov, Leonid M;Dupree, Jeffrey L;Susuki, Keiichiro
• 通讯作者: Susuki, Keiichiro

Sox17 Regulates a Program of Oligodendrocyte Progenitor Cell Expansion and Differentiation during Development and Repair.

Sox17 在发育和修复过程中调节少突胶质细胞祖细胞的扩增和分化程序。

• 发表时间: 2019-12-03
• 影响因子: 8.8
• 作者: Chew, Li;Ming, Xiaotian;McEllin, Brian;Dupree, Jeffrey;Hong, Elim;Catron, Mackenzie;Fauveau, Melissa;Nait;Gallo, Vittorio
• 通讯作者: Gallo, Vittorio

Oxidative Stress Induces Disruption of the Axon Initial Segment.

氧化应激会导致轴突初始段的破坏。

• 发表时间: 2017-11
• 影响因子: 4.7
• 作者: Clark, Kareem;Sword, Brooke A;Dupree, Jeffrey L
• 通讯作者: Dupree, Jeffrey L

Acute neuroinflammation induces AIS structural plasticity in a NOX2-dependent manner.

急性神经炎症以 NOX2 依赖性方式诱导 AIS 结构可塑性。

• 发表时间: 2017-06-08
• 作者: Benusa, S D;George, N M;Sword, B A;DeVries, G H;Dupree, J L
• 通讯作者: Dupree, J L

Sox17 Promotes Oligodendrocyte Regeneration by Dual Modulation of Hedgehog and Wnt Signaling.

Sox17 通过 Hedgehog 和 Wnt 信号的双重调节促进少突胶质细胞再生。

• 发表时间: 2020-10-23
• 影响因子: 5.8
• 作者: Ming, Xiaotian;Dupree, Jeffrey L;Gallo, Vittorio;Chew, Li
• 通讯作者: Chew, Li