Targeting ERK signalling to ameliorate intellectual disability and autism spectrum disorder associated with chromosomal rearrangements at 16p11.2

人类遗传学使我们能够识别与神经发育障碍（NDD），如智力障碍（ID）和自闭症谱系障碍（ASD）相关的特定基因变异。据信，英国有超过1%的人口患有自闭症，这意味着英国可能有超过69.5万人患有自闭症。智力残疾影响了大约2-3%的普通人群，其中至少25%的病例可能是由遗传易感性引起的。目前还没有治愈ASD/ID的方法，也没有药物可以治疗这些疾病的主要症状。该项目旨在提高开发能够逆转这些基因改变影响的药物的机会。ASD/ID最常见的遗传形式是染色体修饰，它会导致一组基因的缺失或重复。有趣的是，重复和缺失患者之间存在着重要的差异，例如代谢变化（在缺失中体重增加而在重复中体重减少的趋势）和颅面异常（缺失与头部尺寸增加有关，而重复与尺寸减小有关）。重要的是，除了ID/ASD之外，重复患者可能更容易出现精神症状。在16p11.2染色体区域有27个不同的基因，但我们目前还不知道它们对病理状态的贡献。我们已经收集了强有力的初步证据，表明其中一个基因MAPK3可能在这些与16p11.2区域相关的ASD/ID形式的发展中发挥重要作用。在这个项目中，我们将通过监测血液中MAPK3的活性来研究MAPK3在重复和缺失患者中的作用。目标是能够使用MAPK3作为帮助诊断和未来治疗的工具。我们还将生成复杂的人类细胞模型和迷你脑制剂，以研究如何使用新型实验药物纠正和可能恢复MAPK3水平。在项目结束时，我们将证明MAPK3是否是诊断和治疗16p11.2重复和缺失患者的有效治疗靶点。

Human genetics has enabled us to identify specific gene variations which are associated with neurodevelopment disorders (NDD) such intellectual disability (ID) and Autism spectrum disorder (ASD). Just over 1% of the UK population are believed to be on the autism spectrum, meaning over 695,000 people in the UK may be autistic. Intellectual disability affects about 2-3% of the general population, with at least 25% of cases likely to be caused by a genetic predisposition.There is currently no cure for ASD/ID and no medications to treat the main symptoms of these disorders. This project aims to improve the chances of developing medicines able to reverse the effects of these genetic alterations. Among the most common genetic forms of ASD/ID lie chromosomal modifications, which cause either a deletion or a duplication of a group of genes. Interestingly, there are important differences between the duplication and the deletion patients such as metabolic changes (tendency to increase weight in the deletion and decrease weight in the duplication) and craniofacial abnormalities (deletion is associated with increased head size whereas the duplication is associated with decreased size). Importantly, duplication patients may be more susceptible to psychotic symptoms in addition to ID/ASD.In the 16p11.2 chromosomal region there are 27 distinct genes but we currently do not know their contribution to the pathological state. We have gathered strong preliminary evidence that one of these genes, MAPK3, may play a prominent role in the development of these ASD/ID forms associated to the 16p11.2 region. In this project, we will investigate the role of MAPK3 in both duplication and deletion patients by monitoring in the blood its activity. The goal is to be able to use MAPK3 as a tool to help both diagnosis and future treatments.We will also generate sophisticated human cellular models and mini-brain preparations to study how MAPK3 levels can be corrected and possibly restored using novel experimental drugs.At the end of the project we will have demonstrate whether MAPK3 is a valid therapeutic target for the diagnosis and the treatment of 16p11.2 duplication and deletion patients.