Attenuating microglial-dependent axonal pathology in EAE

项目摘要： 近30，000名美国退伍军人在VA系统中接受多发性硬化症（MS）治疗，这是一种致残性疾病 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理解驱动MS的病理机制， 以开发新的更好的治疗方案。MS被经典地描述为脱髓鞘疾病 其中髓磷脂损失伴随着轴突损伤和不可逆的神经功能障碍。占上风的- 研究主题是MS中的轴突病理学是慢性、长期脱髓鞘的结果。尽管轴突- al病理学明确的结果，长期髓鞘损失，我们提出，轴突病理学也是一个主要的 MS中发生于疾病早期且独立于脱髓鞘的事件。支持这一观点的是轴突 在正常外观的白色和灰质中均观察到病理学; MS斑块负荷不相关 伴有轴突损失;在缺乏髓鞘损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，并且发生在疾病的早期阶段，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， 我们的研究结果表明，轴突起始段（AIS），髓鞘裸露的，轴突起始区的MS模型。 负责动作电位的启动和调节，是特异性靶向的促炎，反应， 在没有髓鞘损失的情况下，导致随后的AIS破坏的活性小胶质细胞。此外，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，而且还导致- 艾德改善AIS破坏和AIS恢复。这些发现的临床相关性是支持- 艾德通过我们最近的观察表明，类似的AIS中断也发生在MS中。 研究结果，我们的工作假设是，在MS反应性小胶质细胞迁移到损伤线索，并经历莫尔， 病理变化导致与AIS接触增加，促进促炎因子的靶向， 独立于脱髓鞘促进AIS破坏的因子。此外，我们认为抑制小胶质细胞 与AIS的反应和相互作用将导致AIS的保存和恢复。在这里，我们提出强 初步数据表明，细胞粘附分子神经成束蛋白（Nfasc）的一种新亚型介导了小胶质细胞 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1.抑制小胶质细胞迁移、监视和细胞因子 分泌通过破坏肌动蛋白动力学和2.导致EAE中AIS的结构和功能保留。

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.