Mechanisms of Motor Neuron Injury in Acute Flaccid Myelitis

急性弛缓性脊髓炎运动神经元损伤的机制

• 批准号: 10654840
• 负责人: Matthew J Elrick
• 金额: $ 23.44万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654840
• 关键词: Affect; Animal Model; Biological Models; Cell Death; Cellular biology; Child; Clinical; Clinical Data; Coculture Techniques; Communicable Diseases; Complement; Data; Development; Diagnosis; Disease; Disease Outbreaks; Disease model; Electrophysiology (science); Enterovirus; Enterovirus 68; Enterovirus Infections; Environment; Event; Functional disorder; Future; Genetic; Genetic Variation; Health Benefit; Human; Immune; In Vitro; Incidence; Infection; Injury; Integration Host Factors; Knowledge; Lead; Link; Mediating; Methods; Microscopy; Modeling; Morbidity - disease rate; Morphology; Motor; Motor Neurons; Muscle Fibers; Nature; Neurodegenerative Disorders; Neurologic Symptoms; Neuromuscular Junction; Neuronal Dysfunction; Neurons; Neurosciences; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Onset of illness; Paralysed; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Poliomyelitis; Predisposition; Prevalence; Prevention; Protease Inhibitor; Public Health; RNA Transport; Recovery; Recurrence; Resolution; Role; Spinal; Structure; Study models; Susceptibility Gene; System; Therapeutic; Training; United States; Vertebral column; Viral; Work; acute flaccid myelitis; data modeling; effective therapy; epidemiologic data; experimental study; induced pluripotent stem cell; insight; motor neuron function; motor neuron injury; nervous system disorder; neuron loss; neuroprotection; neurotoxicity; new therapeutic target; novel; nucleocytoplasmic transport; permissiveness; pharmacologic; prevent; protein transport; therapeutic target; virology

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.

项目摘要/摘要 急性弛缓性脊髓炎运动神经元损伤机制的研究 急性弛缓性脊髓炎(AFM)是一种类似于脊髓灰质炎的运动神经元感染性疾病。原子力显微镜 主要影响儿童并产生悲惨后果，往往导致终生瘫痪。令人担忧的是， AFM的发病率随着最近的每一次疫情都呈指数级增长。有效的治疗选择 缺乏原子力显微镜，主要是因为我们对疾病的发病机制缺乏了解。在建议的工作中，我 将在原子力显微镜中研究运动神经元毒性的机制。大多数AFM病例是由 肠道病毒D68(EV68)。因此，我将重点介绍EV68对运动神经元的感染，作为AFM的模型。 首先，我将评估核质转运在EV68感染后运动神经元毒性中的作用。 已知这一途径在肠道病毒感染中发生改变，也是运动神经元的关键决定因素。 神经退行性疾病的毒性。我将进一步定义核孔破裂的机制 EV68的复合体对核质转运和运动神经元毒性的影响以及是否可以 药理上以防止运动神经元在体外死亡为目标。第二，更好地定义病理 EV68感染后的级联，我将在一个新的共培养系统中调查早期病理事件 包括运动神经元和肌肉纤维。我将专门研究运动神经元的形态变化， 电生理活性和神经肌肉连接的完整性。第三，我将确定宿主是否遗传了 背景通过研究iPS运动神经元影响EV68感染性或随后的运动神经元毒性 来自AFM患者与非相关对照的比较。总的来说，这些研究将推动我们的 了解EV68相关AFM的致病机制并评估可能的治疗靶点。 这些实验还将开发和改进用于原子力显微镜研究的模型系统，并产生重要的 为未来导致科学独立的研究提供初步数据。培训计划将提供新的 培训病毒学方法，并扩展我在基于iPS的神经疾病建模和高级 显微镜。