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The role of microRNA regulation in a Drosophila model of Huntington disease

microRNA 调控在亨廷顿病果蝇模型中的作用

基本信息

批准号：
MR/S011609/1
负责人：
Claudio Alonso
金额：
$ 78.7万
依托单位：
University of Sussex
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：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FS011609%2F1
关键词：
role microRNA regulation Drosophila model

项目摘要

The overall goal of this proposal is to determine the roles played by small non-coding RNAs in Huntington Disease (HD), an incurable neurodegenerative disease and the most common monogenic neuropathology in the developed world. HD manifests as a combination of motor, cognitive and behavioural features which deteriorate the patient's physical and mental abilities, ultimately leading to death. Recent studies in humans (Hoss et al., 2014) have demonstrated that many small non-coding RNAs (microRNAs, miRNAs) show differential expression in HD brains suggesting that miRNAs may be involved in the development of HD pathology or be part of a cellular compensatory mechanism that combats the disease. This project investigates these important and timely questions using a Drosophila model of HD. The work will be focused on two central questions:Q1: What are the molecular mechanisms that trigger miRNA dysregulation in HD?Q2: What are the mechanisms that link HD-related miRNA dysregulation to neural dysfunction?The project will be developed as a novel collaboration between Prof. Claudio Alonso at the University of Sussex and Prof. Gillian Bates, FRS at UCL. The Alonso lab is an international leader in the study of the neural roles of miRNAs in Drosophila and Prof. Bates is a world authority in the molecular cellular biology of HD and an expert in mammalian models of HD. The highly complementary nature of our team puts us in an excellent position to determine the roles played by miRNA regulation in a Drosophila model of HD while keeping close to the context of mammalian models of this disease. The project fits the core remit of the MRC Neuroscience and Mental Health Board on "understanding of the mechanisms of neurodegeneration and disorders of the motor system" and will also contribute to advance current models on the molecular control of "the physiology of the nervous system in health and illness".

这项提案的总体目标是确定小非编码RNA在亨廷顿病(HD)中所起的作用，HD是一种无法治愈的神经退行性疾病，也是发达国家最常见的单基因神经病理。HD表现为运动、认知和行为特征的组合，这些特征会恶化患者的身体和精神能力，最终导致死亡。最近对人类的研究(Hoss等人，2014)表明，许多小的非编码RNAs(microRNAs，miRNAs)在HD大脑中显示差异表达，这表明miRNAs可能参与HD病理的发展，或者是对抗疾病的细胞补偿机制的一部分。这个项目使用果蝇的HD模型来研究这些重要和及时的问题。这项工作将集中在两个核心问题上：问题1：在HD中触发miRNA失调的分子机制是什么？问题2：是什么机制将HD相关的miRNA失调与神经功能障碍联系起来？该项目将作为苏塞克斯大学的克劳迪奥·阿隆索教授和伦敦大学学院的吉莉安·贝茨教授之间的一个新的合作项目而发展。阿隆索实验室在研究果蝇miRNAs的神经作用方面处于国际领先地位，贝茨教授是HD分子细胞生物学方面的世界权威，也是HD哺乳动物模型的专家。我们团队的高度互补性使我们处于有利地位，可以确定miRNA调控在果蝇HD模型中所起的作用，同时密切了解这种疾病的哺乳动物模型的背景。该项目符合MRC神经科学和精神健康委员会关于“了解神经退化和运动系统障碍的机制”的核心职责，并将有助于推进当前关于“健康和疾病中神经系统的生理学”的分子控制模型。