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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

基本信息

批准号：
10523887
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
项目类别：
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/10523887
关键词：
Affect Animal Model Biological Models Cell Death Cellular biology Cessation of life 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 Neurosciences Nuclear Pore Complex Nuclear Pore Complex Proteins Onset of illness Paralysed Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Pattern Peptide Hydrolases Pharmacology Poliomyelitis Prevalence Prevention Protease Inhibitor Public Health RNA Transport Recovery Recurrence Resolution Role Spinal Structure Study models Susceptibility Gene System Therapeutic Training United States Viral Work acute flaccid myelitis base data modeling effective therapy epidemiologic data experimental study induced pluripotent stem cell insight motor neuron function motor neuron injury nervous system disorder neuron loss neurotoxicity new therapeutic target novel nucleocytoplasmic transport prevent protein transport therapeutic target virology

项目摘要

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.

项目总结/文摘