Modeling host susceptibility factors in Acute Flaccid Myelitis

急性弛缓性脊髓炎宿主易感因素建模

• 批准号: 10217936
• 负责人: Matthew J Elrick
• 金额: $ 8.15万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2022-01-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217936
• 关键词: Acute; Affect; Biological Assay; Biological Models; Biology; Cell Death; Cell Line; Cells; Characteristics; Child; Clinical; Communities; Data; Development; Disease; Disease Outbreaks; Enterovirus; Enterovirus 68; Enterovirus Infections; Epidemiology; Face; Fibroblasts; Functional disorder; Future; Genetic; Growth; Health Benefit; Human; In Vitro; Incidence; Infection; Injury; Integration Host Factors; Knowledge; Laboratories; Lead; Limb structure; Link; Methods; Minority; Modeling; Molecular Biology; Morbidity - disease rate; Motor Neurons; Mus; Neurobiology; Neurons; Neuropathogenesis; Outcome; Paralysed; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Poliomyelitis; Predisposition; Prevalence; Protocols documentation; Public Health; Reproducibility; Research; Resources; Respiratory Failure; Respiratory Muscles; Sampling; Skin; Spinal; Stress; Symptoms; Syndrome; Therapeutic; Tissues; United States; Viral; Virus Diseases; Work; acute flaccid myelitis; acute infection; base; c-myc Genes; cell type; effective therapy; endoplasmic reticulum stress; excitotoxicity; experimental study; human disease; in vivo; induced pluripotent stem cell; mitochondrial dysfunction; nervous system infection; neuron loss; neurotropic; novel therapeutic intervention; nutrient deprivation; pluripotency; respiratory; stressor; therapeutic target; tissue culture; treatment strategy

Project Summary/Abstract Modeling host susceptibility factors in Acute Flaccid Myelitis Acute flaccid myelitis (AFM) is a poliomyelitis-like neuroinfectious illness of children whose prevalence has increased dramatically in recent years, occurring in biennial outbreaks in the Unites States since at least 2014. The consequences of AFM are often severe and debilitating lifelong paralysis that may also include respiratory failure. Despite its striking similarity to polio, little is known about disease pathogenesis and few effective treatment options exist. AFM has been connected to neurotropic non-polio enteroviruses, especially Enterovirus D68 (EV68). However, the vast majority of cases of EV68 infections cause mild non-specific viral symptoms or a respiratory syndrome, while only a small minority of patients become paralyzed as a result of spinal motor neuron infection. This observation suggests that the development of AFM requires the intersection of viral infection and host factors that are permissive to neuropathogenesis. We will therefore generate induced pluripotent stem cell (iPS) lines from tissues previously donated by AFM patients, and use these to model AFM resulting from EV68 infection in vitro. The initial experiments within the scope of this application will focus on spinal motor neurons, due to the fact that motor neuron death is the proximate cause of paralysis in AFM patients, and evidence for direct motor neuron infection by EV68. We will characterize the composition and reproducibility of AFM patient derived and control iPS lines differentiated into spinal motor neurons, and determine the baseline susceptibility of the neurons to a variety of cellular stressors. These studies will set the stage for future experiments of EV68 infection of patient-derived iPS motor neurons to better understand host factors that are permissive of viral infection and motor neuron death and dysfunction. The result of this work will be a model system for AFM that faithfully reproduces the affected cell type, in human cells, and on a genetic background with proven susceptibility to disease. The iPS lines will also be capable of modeling other disease-relevant cell types in the future. These cell lines will represent a unique and valuable resource to the AFM research community.

项目总结/摘要 急性弛缓性肌炎中宿主易感因素的建模 急性弛缓性肌萎缩症（AFM）是一种小儿脊髓灰质炎样神经感染性疾病，其患病率 近年来急剧增加，至少自2014年以来，美国每两年爆发一次。 AFM的后果通常是严重的和使人衰弱的终身瘫痪，还可能包括呼吸系统疾病。 失败尽管它与脊髓灰质炎惊人的相似，但对疾病的发病机制知之甚少， 存在治疗选择。AFM与嗜神经性非脊髓灰质炎肠道病毒有关， 肠道病毒D 68（EV 68）。然而，绝大多数EV 68感染病例引起轻度非特异性病毒感染， 症状或呼吸系统综合征，而只有少数患者因 脊髓运动神经元感染这一观察表明，原子力显微镜的发展需要 病毒感染和允许神经发病的宿主因素的交叉。因此我们将 从AFM患者先前捐献的组织产生诱导多能干细胞（iPS）系，并使用 这些用于模拟由EV 68体外感染引起的AFM。在此范围内的初步实验 应用将集中在脊髓运动神经元，由于运动神经元死亡是近因， AFM患者瘫痪，以及EV 68直接运动神经元感染的证据。我们将描述 AFM患者衍生的和对照iPS系分化成脊髓运动细胞的组成和再现性 神经元，并确定神经元对各种细胞应激源的基线易感性。这些 这些研究将为EV 68感染患者来源的iPS运动神经元的未来实验奠定基础， 更好地了解允许病毒感染和运动神经元死亡和功能障碍的宿主因素。 这项工作的结果将是一个模型系统的原子力显微镜，忠实地复制受影响的细胞类型， 人类细胞，并在遗传背景上证明对疾病的易感性。iPS系列还将 在未来能够模拟其他疾病相关的细胞类型。这些细胞系将代表一种独特的， AFM研究社区的宝贵资源。