ERA-NET NEURON: Investigation of the neuroinflammatory basis of the human type I

Aicardi-Goutières综合征（AGS）是儿童非常严重的脑部疾病的原因。有很多证据表明，这种脑损伤是由于炎症过程中产生的一种叫做干扰素的化学物质。干扰素通常是由细胞对病毒感染做出反应而产生的，一些患有AGS的儿童最初被误诊为患有病毒相关疾病，因为这些状态的临床重叠密切。与继发于病毒的干扰素的产生相反，AGS由于原发性遗传缺陷而产生过量的干扰素。由于病情的严重性，迫切需要开发新的AGS治疗方法。我们认为，如果我们更好地理解相关的基因变化是如何驱动干扰素产生的，这应该是可能的。我们打算使用最新的基因和细胞技术来了解AGS中的炎症是如何损害脑细胞的。AGS是罕见的，很少有父母觉得能够同意死后，如果他们受影响的孩子死亡。然而，一个有双胞胎女儿的家庭慷慨地捐赠了他们最近去世的女儿的大脑。这种几乎独一无二的资源将使我们能够比以往任何时候都更详细地研究人类神经组织，并使用以前没有的新技术。此外，我们将利用最先进的方法在试管中产生“脑细胞”-来自AGS患者的细胞，这样我们就可以在几种不同的AGS基因亚型的背景下研究脑组织。我们还打算分析一种与AGS相关的基因发生变化的小鼠品系，作为试图了解人类疾病的另一种方法。尽管AGS很罕见，但与疾病相关的基因和蛋白质的研究已成为非常高的科学重要性-部分原因是这些基因/蛋白质参与了人体对HIV-1感染的反应（导致艾滋病的病毒），也是因为一种疾病，身体攻击自己-所谓的自身免疫。因此，我们的工作不仅与受这种可怕状况影响的儿童和家庭有关，而且还可能与更广泛的人类医学疾病有关。

Aicardi-Goutières syndrome (AGS) is a cause of very severe brain disease in children. A lot ofevidence exists to indicate that this brain damage is due to an inflammatory process involving theproduction of a chemical called interferon. Interferon is normally produced by cells in response toinfection by a virus, and some children with AGS are initially misdiagnosed as having a viral-related disease because of the close clinical overlap of these states. In contrast to the production of interferonsecondary to virus, in AGS an excess of interferon occurs due to a primary genetic defect. Because ofthe severity of the condition there is an urgent need to develop new treatments for AGS. We think thisshould be possible if we better understand how the responsible genetic changes drive interferonproduction.We intend to use the very latest genetic and cell technologies to understand how brain cells aredamaged by inflammation in AGS. AGS is rare, and few parents feel able to agree to post-mortem iftheir affected child dies. However, a family with affected twin girls has generously donated the brain ofone of their very recently deceased daughters. This almost unique resource will allow us to studyhuman neurological tissue in more detail than ever before, and using new techniques which have notbeen available previously. Additionally, we are going to make use of state-of-the-art methods forproducing 'brain cells' in a test-tube - derived from cells of patients with AGS, so that we can studybrain tissue in the context of several different genetic sub-types of AGS. We also intend to analyse astrain of mouse which has changes in one of the AGS-related genes as another approach to trying tounderstand the human disease.Although AGS is rare, the study of the genes and the proteins related to the disease has become ofvery high scientific importance - partly because of the involvement of these genes / proteins in howthe body reponds to infection by HIV-1 (the virus that causes AIDS), and also because of an overlapwith diseases where the body attacks itself - so-called autoimmunity. Thus, not only will our work be relevant to the children and families affected by this dreadful condition, it may also have relevance for a much wider set of human medical disorders.