Attenuating microglial-dependent axonal pathology in EAE

项目总结： 近30,000名美国退伍军人正在退伍军人管理局接受多发性硬化症(MS)的治疗，多发性硬化症是一种致残疾病 这会导致运动、感觉和认知功能障碍。没有治愈方法，治疗效果有限。 我实验室的总体目标是更好地了解推动多发性硬化症的病理机制。 以开发新的更好的治疗方案。多发性硬化症被经典地描述为脱髓鞘障碍。 髓鞘丢失伴有轴突损伤和不可逆转的神经功能障碍。大势所趋- ING的主题是MS的轴突病理是慢性、长期脱髓鞘的结果。尽管轴突- ALL病理明显是长期髓鞘丢失的结果，我们认为轴突病理也是主要的 多发性硬化症中的一种事件，发生在疾病早期，与脱髓鞘无关。支持这个想法，轴突 正常的白质和灰质均可观察到病理改变；MS斑块负荷与此无关 有轴突丢失；在缺乏髓鞘丢失的区域轴突数量减少。为了进一步支持轴突 损伤的发生与髓鞘丢失无关，而且在疾病的早期阶段，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)小鼠的主要事件 我们的研究结果表明，轴突起始段(AIS)，即AX的髓鞘裸露的起始区， On负责动作电位的启动和调节，是促炎、反应和... 在没有髓鞘丢失的情况下，活动的小胶质细胞导致随后的AIS中断。此外，我们还展示了 抗炎治疗不仅减少了小胶质细胞的反应性和小胶质细胞/AIS的接触，而且还导致了- ED在改善AIS中断和AIS恢复方面的作用。这些发现的临床相关性是支持- 我们最近的观察表明MS中也发生了类似的AIS中断，这一点基于我们的 我们的工作假设是，在多发性硬化症中，反应性小胶质细胞向损伤线索迁移，并经历更多- 病理改变导致与AIS接触增加，促进促炎因子的靶向- TORS促进AIS的破坏，不依赖于脱髓鞘。此外，我们认为对小胶质细胞的抑制 响应和与AIS的互动将导致AIS的保存和恢复。在这里，我们展示了强大的 一种新的细胞黏附分子神经束蛋白(NFasc)亚型介导小胶质细胞的初步研究 在EAE的MS模型中的响应。基于我们的发现和其他NFasc亚型的已知功能，我们 预测NFasc的小胶质细胞特异性消融将抑制小胶质细胞的迁移、监视和细胞因子。 通过扰乱肌动蛋白的动态分泌，以及2.导致EAE中结构和功能的AIS保存。

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.