The Role of RanBP2 in the pathogenesis of acute necrotizing encephalopathy

项目总结

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.