Regulation and resilience of the neuronal microtubule cytoskeleton in health and disease

健康和疾病中神经元微管细胞骨架的调节和恢复能力

• 批准号: MR/Y000633/1
• 负责人: Carolyn Moores
• 金额: $ 207.46万
• 依托单位: Birkbeck, University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY000633%2F1
• 关键词: Regulation; resilience; neuronal; microtubule; cytoskeleton

Our brains are built from billions of specialised cells called neurons. The many complex tasks that our brains perform, including thought and memory, occur because neurons make connections with each other that allow them to communicate. Early in brain development, immature neurons are not connected to each other and must navigate to exactly the right position to correctly integrate into the brain's communication network. Healthy brain function throughout our lives depends on the connections between our neurons being well maintained. Severe human diseases can occur if neuron connectivity and operation breaks down at any stage. Inaccurate neuron movement during brain development can cause intellectual disability, epilepsy and early death. Incomplete maintenance of neuronal function as our brains mature into adulthood can also cause neuropsychiatric illnesses including schizophrenia. Breakdown of neuronal function as we age can cause neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). In all these disease scenarios, there remains much to learn, and work in my lab is seeking to understand the machinery that supports neuronal health during development and as we mature.In the same way as our body has a skeleton that provides us with support and strength, neurons have a skeleton - called the cytoskeleton - which also gives them support and strength. The cytoskeleton is involved in many important aspects of neuronal life, and is part of the machinery that drives neuron movement during development, along with maintenance of connectivity and communication in mature neurons. Breakdown or disruption of the neuronal cytoskeleton is associated with developmental syndromes, neurodegenerative diseases and neuropsychiatric illnesses. Studying the cytoskeleton machinery is important so we can understand both how healthy neurons operate and how machinery malfunction causes disease.This project will focus on a part of the cytoskeleton called microtubules. These are long cylindrical structures that act like scaffolding inside the neuron and also act as tracks along which molecular transport motors carry cargo within the neuron. The organisation and stability of the microtubule machinery, together with the particular type of cargo that is carried along it, defines how the neuron functions. We would like to understand how the neuronal microtubules are assembled and maintained to help neurons undertake their many complex tasks within the brain. My research team studies the three-dimensional structure of microtubules, because knowing what they look like can help us understand how they work. We use a very powerful microscope called an electron microscope to take pictures of individual microtubules that have either been assembled in a test tube or form within a living neuron. We then use computers to combine these electron microscope pictures to calculate the microtubules' three-dimensional shape. By using information from patients with diseases that disrupt the microtubule machinery, we will be able to map disease-causing defects to particular machinery components.In the future, knowledge arising from our work may allow us to target and repair the broken parts of the cytoskeleton machinery in diseased or damaged neurons. Such understanding could also shed light on new treatments for dementia, stroke and physical injury.

我们的大脑是由数十亿个称为神经元的专门细胞建造的。我们的大脑执行的许多复杂任务，包括思想和记忆，是因为神经元之间的连接使它们可以交流。在大脑发育的早期，未成熟的神经元与彼此没有连接，并且必须准确地导航到正确地集成到大脑的通信网络中。一生中健康的大脑功能取决于神经元维护良好之间的联系。如果神经元连通性和操作在任何阶段分解，可能会发生严重的人类疾病。大脑发育过程中神经元运动不准确会导致智力残疾，癫痫和早期死亡。神经元功能不完整，因为我们的大脑成熟到成年，也可能导致包括精神分裂症在内的神经精神疾病。随着年龄的增长，神经元功能的分解会引起神经退行性疾病，例如肌萎缩性侧面硬化症（ALS）。在所有这些疾病的情况下，仍然有很多东西要学习，我的实验室工作正在寻求了解在发育过程中以及我们成熟的神经元健康的机械。以我们的身体具有为我们提供支撑和力量的骨骼相同的方式，神经元具有一个骨架 - 称为细胞骨骼 - 也为他们提供了支持和力量。细胞骨架参与了神经元生活的许多重要方面，并且是驱动发育过程中神经元运动的机械的一部分，以及维持成熟神经元中连通性和通信的维持。神经元细胞骨架的分解或破坏与发育综合征，神经退行性疾病和神经精神疾病有关。研究细胞骨架机械非常重要，因此我们可以了解健康的神经元如何操作以及机械故障如何引起疾病。该项目将重点放在一个称为微管的细胞骨架上。这些是长的圆柱结构，就像在神经元内的脚手架一样起作用，并且还充当了分子传输电动机在神经元内携带货物的轨道。微管机械的组织和稳定性以及沿其携带的特定类型的货物定义了神经元的功能。我们想了解如何组装和维护神经元微管，以帮助神经元在大脑中执行许多复杂的任务。我的研究团队研究了微管的三维结构，因为知道它们的外观可以帮助我们了解它们的工作方式。我们使用称为电子显微镜的非常强大的显微镜来拍摄单个微管的照片，这些微管要么在活神经元内组装或形式。然后，我们使用计算机将这些电子显微镜图片组合在一起，以计算微管的三维形状。通过使用破坏微管机械疾病患者的信息，我们将能够将引起疾病的缺陷映射到特定的机械组件。未来，我们的工作引起的知识可能使我们可以针对和修复患病或受损神经元的细胞骨架机械的破裂部分。这种理解还可以阐明痴呆症，中风和身体损伤的新治疗方法。