The Role of RanBP2 in the pathogenesis of acute necrotizing encephalopathy

项目摘要 急性坏死性脑病是一种破坏性的神经系统疾病，与 系统性感染，包括流感和新冠肺炎的病原体SARS-CoV2。在或期间 就在感染之后，受影响的人会在多个脑区出现损害，并迅速发展。 意识的改变，癫痫发作和昏迷。这种疾病优先影响儿童，并且 大约三分之一受影响的人死亡。所有幸存者中有一半留下了大量的身体和 认知障碍。 关于ANE是如何产生的，人们知之甚少。炎性分子的增加--称为 已经注意到患者血液和脊髓液中的细胞因子，导致了一种假设 “细胞因子风暴”起着重要作用。已经在一种蛋白质中发现了一种基因突变，这种突变可以将 但这种突变如何影响脑细胞，以及它可能如何与 炎症反应仍不清楚。 在这里，我们提出了一种基于人类诱导的多能干细胞的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，而不是与疾病相关性较小的啮齿动物模型。我们 预计我们的模型的建立将产生对ANE如何产生以及将如何产生的初步见解 最终导致制定预防或治疗措施来对抗这种情况 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.