A neurodevelopmental origin of dystonia

肌张力障碍的神经发育起源

• 批准号: MR/V03118X/1
• 负责人: James Jepson
• 金额: $ 189.88万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV03118X%2F1
• 关键词: neurodevelopmental; origin; dystonia

Maintaining control over bodily movements is critical for our wellbeing. Many neurological diseases, however, result in a loss of such control, diminishing quality of life. Here, I focus on one such disease that is prevalent yet poorly understood: dystonia. Dystonia is characterised by involuntary muscle contractions that result in twisted, contorted postures. Over 90,000 patients in the UK alone suffer from this disease. Dystonic movements are frequently painful and may begin at an early age - in some cases, just weeks after birth. Furthermore, dystonia is often associated with additional disease symptoms, including other movement disorders such as Parkinsonism, ataxia, dyskinesia, and myoclonus; and non-movement-related disorders such as epilepsy, autism, intellectual disability and developmental delay. Unfortunately, therapeutic options to treat dystonia are limited. This is primarily due to a lack of understanding regarding the fundamental molecular and cellular basis of involuntary movements in this disorder. In this Fellowship application, I describe a series of approaches to uncover such mechanisms using the fruit fly, Drosophila melanogaster - a model organism with unparalleled rapidity of use and a hugely powerful toolkit that readily enables manipulations of both genes and neural circuits. I introduce a novel Drosophila model of dystonia; demonstrate that this model exhibits dystonia-like alterations in movement and the activity of neural circuits that influence movement; and show how this model can be used to uncover cellular pathways that cause dystonia. I propose to confirm the broader relevance of our findings by generating a new array of Drosophila dystonia models, and to utilise these models to identify novel drug treatments. Furthermore, I have built a unique network of national and international collaborators specialising in the study of dystonia genetics, neurophysiology, and mouse models of the disease. This network will allow me to greatly increase translational impact by using our results to guide studies in human and mammalian systems, to confirm the validity of potential drug treatments in mammalian dystonia models. Implementation of my experimental strategy promises to greatly enhance our understanding of how dystonic movement arise, and uncover novel therapeutic methods to treat this debilitating disorder. Achieving these goals may also shed light on the large number of neurological diseases that are frequently co-morbid with dystonia.

保持对身体活动的控制对我们的健康至关重要。然而，许多神经系统疾病会导致这种控制的丧失，从而降低生活质量。在这里，我将重点介绍一种流行但知之甚少的疾病：肌张力障碍。肌张力障碍的特征是肌肉不自主收缩，导致扭曲、扭曲的姿势。仅在英国就有超过9万名患者患有这种疾病。肌张力障碍运动经常是痛苦的，可能在很小的时候就开始了--在某些情况下，只在出生后几周就开始了。此外，肌张力障碍通常与其他疾病症状有关，包括其他运动障碍，如帕金森症、共济失调、运动障碍和肌阵挛；以及非运动相关疾病，如癫痫、自闭症、智力残疾和发育迟缓。不幸的是，治疗肌张力障碍的治疗选择有限。这主要是由于缺乏对这种疾病中非自主运动的基本分子和细胞基础的了解。在这份奖学金申请中，我描述了一系列使用果蝇揭示这种机制的方法，果蝇是一种具有无与伦比的使用速度的模式生物，它是一个非常强大的工具包，可以轻松地操纵基因和神经电路。我介绍了一种新的肌张力障碍的果蝇模型；证明了该模型在运动中表现出类似肌张力障碍的变化以及影响运动的神经回路的活动；并展示了该模型如何用于揭示导致肌张力障碍的细胞通路。我建议通过生成一系列新的果蝇肌张力障碍模型来确认我们的发现的更广泛的相关性，并利用这些模型来确定新的药物治疗方法。此外，我还建立了一个由国内和国际合作者组成的独特网络，专门研究肌张力障碍遗传学、神经生理学和疾病的小鼠模型。这个网络将使我能够通过使用我们的结果来指导在人类和哺乳动物系统中的研究，以确认潜在的药物治疗在哺乳动物肌张力障碍模型中的有效性，从而极大地增加翻译影响。我的实验策略的实施有望极大地提高我们对肌张力障碍运动如何产生的理解，并发现治疗这种衰弱障碍的新的治疗方法。实现这些目标还可能有助于了解大量经常与肌张力障碍并存的神经系统疾病。