The Role of RanBP2 in the pathogenesis of acute necrotizing encephalopathy

RanBP2在急性坏死性脑病发病机制中的作用

基本信息

批准号：
10190405
负责人：
ARUN VENKATESAN
金额：
$ 45.03万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10190405
关键词：
2019-nCoV Accounting Acute Adult Affect Area Astrocytes Axon Biological Biological Models Biology Blood Brain COVID-19 Cell Death Cell physiology Cerebrospinal Fluid Child Coma Conscious DNA Sequence Alteration Development Disease Disease model Embryo Encephalopathies Event Exhibits Functional disorder Genetic Predisposition to Disease Health Human Individual Infection Infiltration Inflammation Inflammatory Inflammatory Response Influenza Injury Knock-out Lead Left Lesion Leucine Link Maintenance Measures Mediating Mediator of activation protein Missense Mutation Mitochondria Modeling Molecular Mus Mutation N-terminal Necrosis Nervous System Trauma Neuraxis Neurobiology Neurologic Neuronal Dysfunction Neuronal Injury Neurons Neuropathogenesis Nuclear Pore Complex Nuclear Pore Complex Proteins Pathogenesis Pathway interactions Patients Pattern Play Positioning Attribute Predisposition Proteins Regulation Risk Rodent Model Role Seizures Serum Supporting Cell Survivors System Systemic infection Therapeutic Viral axon injury base brain cell cell type cognitive disability combat cytokine cytokine release syndrome disease-causing mutation effective therapy experimental study extracellular gray matter induced pluripotent stem cell influenzavirus insight mutant neuron loss novel nucleocytoplasmic transport pathogen physically handicapped pleiotropism protein function relating to nervous system response stem cell based approach stem cell model

项目摘要

Project Summary Acute necrotizing encephalopathy (ANE) is a devastating neurologic condition associated with systemic infections, including influenza and SARS-CoV2, the causative agent of Covid-19. During or just following infection, affected individuals develop lesions in multiple brain areas and rapidly develop changes in consciousness, seizures, and coma. The disorder preferentially affects children, and about one third of affected individuals die. Half of all survivors are left with substantial physical and cognitive disability. Little is known about how ANE arises. An increase in inflammatory molecules – termed cytokines- in the blood and spinal fluid of patients has been noted, leading to the hypothesis that a “cytokine storm” plays a major role. A genetic mutation has been identified in a protein that places individuals at risk for ANE, but how that mutation affects brain cells and how it may be related to the inflammation remains unclear. Here, we propose to develop a model of ANE based on human induced pluripotent stem cell based approaches. The advantages of this model are that we will be able to study human neurons and supporting cells, as opposed to rodent models that may be less relevant to the disease. We anticipate that establishment of our model will yield initial insights into how ANE arises and will eventually lead to the development of preventative or therapeutic measures to combat this devastating disorder.

项目摘要急性坏死性脑病（ANE）是与与之相关的毁灭性神经系统疾病全身感染，包括影响力和SARS-COV2，是COVID-19的致病药物。期间就在感染后，受影响的个体在多个大脑区域发展并迅速发展意识，癫痫发作和昏迷的变化。这种疾病优先影响儿童，以及大约三分之一的受影响的人死亡。一半的幸存者都有大量的身体和认知障碍。关于ANE的出现知之甚少。炎症分子的增加 - 称为细胞因子 - 已经注意到患者的血液和脊髓液，导致假设是 “细胞因子风暴”起着重要作用。在位置的蛋白质中已经发现了遗传突变具有ANE风险的个体，但是该突变如何影响脑细胞以及与脑细胞的关系炎症仍然不清楚。在这里，我们建议基于人类诱导的多能干细胞开发ANE模型基于方法。该模型的优点是我们能够研究人类神经元和支持细胞，与可能与疾病无关的啮齿动物模型相反。我们预计我们的模型的建立将产生有关ANE如何出现和将会产生的最初见解甚至导致制定预防或治疗措施来对抗这一点毁灭性疾病。