Mechanisms of Motor Neuron Injury in Acute Flaccid Myelitis

项目总结/摘要 急性弛缓性肌病运动神经元损伤机制的研究 急性弛缓性肌麻痹（AFM）是一种类似脊髓灰质炎的运动神经元感染性疾病。AFM 主要影响儿童，并造成悲惨后果，往往导致终身瘫痪。令人担忧的是， AFM的发病率随着最近的每一次爆发而呈指数增长。的有效治疗选择 缺乏AFM，主要是由于我们对疾病发病机制的理解不足。在工作中，我 将在AFM中研究运动神经元毒性的机制。大多数AFM病例由以下原因引起： 肠道病毒D 68（EV 68）。因此，我将重点放在运动神经元的感染EV 68作为AFM的模型。 首先，我将评估核质转运在EV 68感染后运动神经元毒性中的作用。 已知该途径在肠道病毒感染中改变，并且也是运动神经元的关键决定因素 神经退行性疾病中的毒性。我将进一步定义核孔破裂的机制 EV 68复合物，其对核质转运和运动神经元毒性的影响，以及它是否可以 体外靶向预防运动神经元死亡。第二，为了更好地定义病理性 在EV 68感染后的级联反应中，我将在一种新的共培养系统中研究早期病理事件 包括运动神经元和肌肉纤维。我将专门研究运动神经元形态的变化， 电生理活动和神经肌肉接头完整性。第三，确定宿主是否遗传 通过研究iPS运动神经元，背景影响EV 68感染性或随后的运动神经元毒性 与无关对照相比，来自AFM患者。总的来说，这些研究将推动我们的 理解EV 68相关AFM的致病机制，并评估推定的治疗靶点。 实验还将开发和完善模型系统的研究原子力显微镜和产生重要的 为今后的研究提供初步数据，以实现科学独立性。培训计划将提供新的 在病毒学方法的培训，并扩大我在基于iPS的神经疾病建模和先进的专业知识 显微镜

Project Summary/Abstract Mechanisms of Motor Neuron Injury in Acute Flaccid Myelitis Acute flaccid myelitis (AFM) is an infectious disorder of motor neurons that resembles poliomyelitis. AFM predominantly affects children and has tragic consequences, often leading to lifelong paralysis. Concerningly, the incidence of AFM has increased exponentially with each recent outbreak. Effective treatment options for AFM are lacking, owing primarily to our poor understanding of disease pathogenesis. In the proposed work, I will investigate mechanisms of motor neuron toxicity in AFM. The majority of cases of AFM are caused by Enterovirus D68 (EV68). Therefore, I will focus on the infection of motor neurons by EV68 as a model of AFM. First, I will evaluate the role of nucleocytoplasmic transport in motor neuron toxicity following EV68 infection. This pathway is known to be altered in enterovirus infection and is also a key determinant of motor neuron toxicity in neurodegenerative disease. I will further define the mechanism of disruption of the nuclear pore complex by EV68, its effects on nucleocytoplasmic transport and motor neuron toxicity, and whether it can be pharmacologically targeted to prevent motor neuron death in vitro. Second, to better define the pathologic cascade following EV68 infection, I will investigate early pathologic events in a novel co-culture system including motor neurons and muscle fibers. I will specifically investigate changes in motor neuron morphology, electrophysiologic activity, and neuromuscular junction integrity. Third, I will determine whether host genetic background influences EV68 infectivity or subsequent motor neuron toxicity by studying iPS motor neurons derived from AFM patients compared to unrelated controls. Collectively, these studies will advance our understanding of pathogenic mechanisms in EV68-associated AFM and evaluate putative therapeutic targets. The experiments will also develop and refine model systems for the study of AFM and generate important preliminary data for future studies leading to scientific independence. The training plan will provide new training in virology methods and extend my expertise in iPS-based neurologic disease modeling and advanced microscopy.