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

靶向 ERK 信号传导以改善与 16p11.2 染色体重排相关的智力障碍和自闭症谱系障碍

• 批准号: MR/S037667/1
• 负责人: Riccardo Brambilla
• 金额: $ 181.63万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS037667%2F1
• 关键词: Targeting; ERK; signalling; ameliorate; intellectual

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.

人类遗传学使我们能够识别与神经发育障碍（NDD）相关的特定基因变异，如智力残疾（ID）和自闭症谱系障碍（ASD）。据信，英国只有1%以上的人口属于自闭症谱系，这意味着英国可能有超过695，000人患有自闭症。智力残疾影响大约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。目前没有治疗ASD/ID的方法，也没有治疗这些疾病的主要症状的药物。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最常见的遗传形式之一是染色体修饰，其导致一组基因的缺失或复制。有趣的是，重复和缺失患者之间存在重要差异，例如代谢变化（缺失中体重增加和重复中体重减少的趋势）和颅面异常（缺失与头部大小增加相关，而重复与大小减少相关）。重要的是，重复患者可能更容易患上精神病症状，除了ID/ASD。在16p11.2染色体区域有27个不同的基因，但我们目前不知道他们的病理状态的贡献。我们已经收集了强有力的初步证据表明，这些基因之一，MAPK 3，可能在这些ASD/ID形式的发展中发挥了突出的作用与16p11.2区域。在这个项目中，我们将通过监测血液中MAPK 3的活性来研究MAPK 3在重复和缺失患者中的作用。我们的目标是能够使用MAPK 3作为一种工具，以帮助诊断和未来的治疗。在项目的最后，我们将证明MAPK 3是否是诊断和治疗16p11.2重复的有效治疗靶点和缺失型患者。

项目成果

Regulator of G-Protein Signalling 4 (RGS4) negatively modulates nociceptin/orphanin FQ opioid receptor signalling: Implication for l-Dopa-induced dyskinesia.

G 蛋白信号传导调节器 4 (RGS4) 负向调节伤害感受肽/孤啡肽 FQ 阿片受体信号传导：对左旋多巴诱导的运动障碍的影响。

• DOI: 10.1111/bph.15730
• 发表时间: 2023
• 期刊: British journal of pharmacology
• 影响因子: 7.3
• 作者: Pisanò CA

Nicotine self-administration and ERK signaling are altered in RasGRF2 knockout mice.

• DOI: 10.3389/fphar.2022.986566
• 发表时间: 2022
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6

Dopamine D1 and Glutamate Receptors Co-operate With Brain-Derived Neurotrophic Factor (BDNF) and TrkB to Modulate ERK Signaling in Adult Striatal Slices.

• DOI: 10.3389/fncel.2020.564106
• 发表时间: 2020
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Morella I;Hallum H;Brambilla R
• 通讯作者: Brambilla R

An adapted social communication intervention at home and education to promote social communication change in children with severe autism: the PACT-G RCT

适应家庭和教育的社会沟通干预，以促进严重自闭症儿童的社会沟通改变：PACT-G RCT

• DOI: 10.3310/lbxi2342
• 发表时间: 2022
• 期刊: Efficacy and Mechanism Evaluation
• 作者: Green J