The role of astrocytes in early pathogenesis of motor neuron disease: a mechanistic study of neuronal degeneration and synaptic alterations

星形胶质细胞在运动神经元疾病早期发病机制中的作用：神经元变性和突触改变的机制研究

• 批准号: MR/P008658/1
• 负责人: Andras Lakatos
• 金额: $ 115.95万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP008658%2F1
• 关键词: role; astrocytes; early; pathogenesis; motor

Motor neuron disease (MND) is a rapidly disabling condition, leading to generalized muscle weakness and finally to death most commonly by paralysis of breathing muscles. The patients' quality of life is significantly reduced during the median survival time of three years not only by physical disabilities but also by dementia to a variable degree. In the UK 1 in 300-500 people are at risk of developing this disease, affecting about 5000 people at any time. It is untreatable and there is urgent need to develop successful therapies. In order to achieve this we need to understand the problems occurring in nerve cells, called neurons and also in their surroundings.The immediate issue causing disability is within motor neurons, specialized nerve cells that normally convey electrical impulses to achieve muscle contraction. However, a major breakthrough in MND research identified that glial cells involved in supporting the function of neurons can be diseased too. Astrocytes, a type of glial cell that closely interact with motor neurons, have been shown to directly harm or to disrupt important cross-talk between them, resulting in muscle weakness. These mechanisms commonly occur in MND, providing a logical target for new treatments.Over the last decade as a researcher and practicing neurologist, my work was based on understanding the dialogue between astrocytes and neurons. Establishing a research group at the University of Cambridge, we have made fundamental observations supporting the idea that by default astrocytes are meant to repair damaged motor neurons. Now, I also assembled innovative collaborations to develop my skill-set and to use state-of-art models relevant to human disease to identify what goes wrong in the astrocyte and motor neuron relationship. The ultimate aim of this work is to gain insight that can help us to treat (and even possibly cure) MND.

运动神经元病（MND）是一种快速致残的疾病，导致全身性肌肉无力，最后死亡，最常见的是呼吸肌麻痹。在三年的中位生存期内，患者的生活质量显着降低，不仅是由于身体残疾，而且还由于不同程度的痴呆。在英国，每300-500人中就有1人有患这种疾病的风险，随时影响约5000人。它是无法治愈的，迫切需要开发成功的治疗方法。为了实现这一目标，我们需要了解神经细胞（称为神经元）及其周围环境中发生的问题。导致残疾的直接问题是运动神经元，这些特殊的神经细胞通常传递电脉冲以实现肌肉收缩。然而，MND研究的一项重大突破表明，参与支持神经元功能的神经胶质细胞也可能患病。星形胶质细胞是一种与运动神经元密切相互作用的神经胶质细胞，已被证明直接损害或破坏它们之间的重要串扰，导致肌肉无力。这些机制通常发生在MND中，为新的治疗提供了一个合乎逻辑的目标。在过去的十年中，作为一名研究人员和执业神经学家，我的工作是基于对星形胶质细胞和神经元之间对话的理解。在剑桥大学建立了一个研究小组，我们已经进行了基本的观察，支持星形胶质细胞默认是为了修复受损的运动神经元的想法。现在，我还组织了创新的合作来发展我的技能，并使用与人类疾病相关的最先进的模型来确定星形胶质细胞和运动神经元关系中的问题。这项工作的最终目的是获得可以帮助我们治疗（甚至可能治愈）MND的见解。

项目成果

Cell-Free Mitochondrial DNA in Acute Brain Injury.

• DOI: 10.1089/neur.2022.0032
• 发表时间: 2022
• 期刊: NEUROTRAUMA REPORTS
• 影响因子: 2.4
• 作者: Kayhanian, Saeed;Glynos, Angelos;Mair, Richard;Lakatos, Andras;Hutchinson, Peter J. A.;Helmy, Adel E.;Chinnery, Patrick F.
• 通讯作者: Chinnery, Patrick F.

Cerebral organoids at the air-liquid interface generate diverse nerve tracts with functional output

气液界面的大脑类器官产生具有功能输出的不同神经束

• DOI: 10.1101/353151
• 发表时间: 2018
• 作者: Giandomenico S

Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength.

• DOI: 10.1016/j.neuron.2018.03.010
• 发表时间: 2018-04-18
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Kelley KW;Ben Haim L;Schirmer L;Tyzack GE;Tolman M;Miller JG;Tsai HH;Chang SM;Molofsky AV;Yang Y;Patani R;Lakatos A;Ullian EM;Rowitch DH
• 通讯作者: Rowitch DH

Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength

Kir4.1 依赖性星形胶质细胞与快速运动神经元相互作用是峰值强度所必需的

• DOI: 10.17863/cam.22171
• 发表时间: 2018
• 作者: Kelley K

Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS.

• DOI: 10.1016/j.celrep.2017.05.024
• 发表时间: 2017-05-30
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Hall CE;Yao Z;Choi M;Tyzack GE;Serio A;Luisier R;Harley J;Preza E;Arber C;Crisp SJ;Watson PMD;Kullmann DM;Abramov AY;Wray S;Burley R;Loh SHY;Martins LM;Stevens MM;Luscombe NM;Sibley CR;Lakatos A;Ule J;Gandhi S;Patani R
• 通讯作者: Patani R