The Role of RanBP2 in the pathogenesis of acute necrotizing encephalopathy

项目摘要 急性坏死性脑病（ANE）是一种破坏性的神经系统疾病， 全身性感染，包括流感和SARS-CoV 2，后者是Covid-19的病原体。期间或 感染后，受影响的个体在多个大脑区域出现病变，并迅速发展为 意识改变癫痫和昏迷这种疾病优先影响儿童， 大约三分之一的受影响者死亡。一半的幸存者留下了大量的身体和 认知障碍 关于ANE是如何产生的，我们知之甚少。炎症分子的增加-称为 细胞因子-在患者的血液和脊髓液中已经注意到，导致假设， “细胞因子风暴”起主要作用。在一种蛋白质中发现了基因突变， 个体有ANE的风险，但是这种突变如何影响脑细胞，以及它如何与ANE相关。 炎症仍不清楚。 在此，我们建议建立一个基于人诱导多能干细胞的ANE模型 基于方法。这个模型的优点是我们将能够研究人类神经元 和支持细胞，而不是啮齿动物模型，可能与疾病相关性较低。我们 预计我们模型的建立将产生关于ANE如何产生的初步见解，并将 最终导致预防或治疗措施的发展，以打击这一点， 毁灭性的混乱

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.