The role of talin and vinculin in neuronal mechanosensing.

踝蛋白和纽蛋白在神经元机械传感中的作用。

• 批准号: BB/M020630/1
• 负责人: Christoph Ballestrem
• 金额: $ 39.11万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM020630%2F1
• 关键词: role; talin; vinculin; neuronal; mechanosensing.

During development, billions of neurons form long cellular extensions called axons, which find their way to specific target sites such as other neurons. Through these connections neurons form a highly organised network and transmit information in form of electrical and chemical signals that govern our organ functions. Neurons need to find specific targets not only during the development of the nervous system but also after injury, when they have to regrow through damaged tissue. Failure to reconnect often leads to severe health problems - for example, to date there is no treatment for recovering function after spinal cord injuries. Neuroscience has focused on chemical signals regulating growth and regrowth of neurons for decades, but we are still far from understanding why neurons in human brains and spinal cords do not regenerate.The environment in the brain alters enormously during development, normal ageing, injury and certain diseases. Brain tissue is extremely soft. However, it becomes stiffer during ageing (in men more than in women), and under pathological conditions it can change dramatically in structure and stiffness. Prominent examples are scarring after injury or stroke, and the formation of rigid plaques or tangles in diseases such as Alzheimer's. Neurons sense such mechanical changes in their environment and respond with drastic changes in their behaviour, as best illustrated by the failure of axons to regrow after spinal cord injury due to the presence of scars. Therefore, understanding how neurons respond to their mechanical environment is important if we want to get a step closer to treating, for example, spinal cord injuries.Neurons can feel the stiffness of their environment by exerting forces on it and probing its deformation. In order to transmit forces, they 'grab' neighbouring structures using special proteins, which are called integrins. These integrins not only bind to the environment of the cells but also connect to a skeleton inside the cells. This link is not direct but is regulated by components that couple or uncouple the two. We did some first experiments that suggest that two of these coupling proteins (which are called talin and vinculin) allow neurons to measure the stiffness of their environment, but how they do this is still unclear. In order to investigate how these proteins regulate the neuronal response to their mechanical environment, and to what extent they are involved in telling neurons where to grow, two laboratories in Manchester and Cambridge team up and combine their long-standing expertise with integrins, neurons and forces. The proposed research aims to (i) determine how talin and vinculin transmit mechanical information between the outside world and the inside skeleton, (ii) investigate their role in sensing stiffness differences in the environment of neurons and how this affects neuronal outgrowth and guidance, and (iii) understand how talin and vinculin interact with each other and with another protein named RIAM, which likely explains how mechanical signals control axon outgrowth and pathfinding. To reach our goals, we will not only use cutting edge microscopy, biophysics and molecular biology techniques but also develop new tools to mimic the mechanically altered environmental conditions that neurons encounter. Our results will be combined into a model that outlines and predicts how environmental signals and intracellular processes contribute to neuronal outgrowth and guidance during development, ageing and disease. Ultimately, the knowledge gained may lead to important changes in how we currently treat patients with different neuronal disorders, and it might thus, for example, contribute to successful treatment approaches to spinal cord injuries.

在开发过程中，数十亿个神经元形成了称为轴突的长细胞延伸，这些神经元在特定靶位点（例如其他神经元）中找到了方法。通过这些连接，神经元形成一个高度组织的网络，并以控制我们器官功能的电信和化学信号的形式传输信息。神经元不仅需要在神经系统的发展过程中，而且在受伤后必须通过受损的组织再生长时找到特定的靶标。未能重新连接通常会导致严重的健康问题 - 例如，迄今为止，脊髓损伤后没有恢复功能的治疗方法。神经科学一直集中在数十年来调节神经元生长和再生的化学信号上，但是我们仍然远远不足以理解为什么人类大脑和脊髓中的神经元不会再生。大脑中的环境在发育，正常衰老，损伤和某些疾病期间大大改变。脑组织非常柔软。但是，在衰老期间（男性比在女性中比在女性中）变得更硬，在病理状况下，它可以在结构和僵硬中发生巨大变化。突出的例子是在受伤或中风后发生疤痕，在阿尔茨海默氏病等疾病中形成刚性斑块或缠结。神经元感觉到环境的这种机械变化，并随着其行为的巨大变化做出反应，这是轴突由于疤痕的存在而在脊髓损伤后再生的最佳说明。因此，如果我们想更接近治疗，例如脊髓损伤，了解神经元如何对其机械环境的反应很重要。神经元可以通过在其上施加力并探测其变形来感受到其环境的僵硬。为了传输力，他们使用特殊蛋白质“抓住”相邻结构，称为整联蛋白。这些整联蛋白不仅结合了细胞的环境，而且还连接到细胞内部的骨骼。此链接不是直接的，而是由夫妇或脱离两者的组件来调节。我们进行了一些第一个实验，表明这些耦合蛋白中的两个（称为塔林和vinculin）允许神经元测量其环境的僵硬，但是它们如何做到这一点仍不清楚。为了研究这些蛋白质如何调节对机械环境的神经元反应，以及它们在何种程度上参与告诉神经元在哪里生长，曼彻斯特和剑桥的两个实验室组合在一起，并将其长期的专业知识与整合素，神经元和力相结合。 The proposed research aims to (i) determine how talin and vinculin transmit mechanical information between the outside world and the inside skeleton, (ii) investigate their role in sensing stiffness differences in the environment of neurons and how this affects neuronal outgrowth and guidance, and (iii) understand how talin and vinculin interact with each other and with another protein named RIAM, which likely explains how mechanical signals control axon outgrowth and探路。为了实现我们的目标，我们将不仅使用尖端显微镜，生物物理学和分子生物学技术，而且还将开发新的工具来模仿神经元遇到的机械改变的环境条件。我们的结果将合并为一个模型，概述并预测了环境信号和细胞内过程如何促进神经元的产物和指导，并在发育，衰老和疾病期间。最终，获得的知识可能会导致我们目前治疗不同神经元疾病的患者的重要变化，因此，例如，它可能有助于成功治疗脊髓损伤的方法。

项目成果

Vinculin is required for neuronal mechanosensing but not for axon outgrowth.

纽蛋白是神经元机械传感所必需的，但不是轴突生长所必需的。

• DOI: 10.1016/j.yexcr.2021.112805
• 发表时间: 2021
• 期刊: Experimental cell research
• 影响因子: 3.7
• 作者: Wang DY

Photoresponsive Hydrogels with Photoswitchable Mechanical Properties Allow Time-Resolved Analysis of Cellular Responses to Matrix Stiffening.

• DOI: 10.1021/acsami.7b18302
• 发表时间: 2018-03-07
• 期刊: ACS applied materials & interfaces
• 影响因子: 9.5
• 作者: Lee IN;Dobre O;Richards D;Ballestrem C;Curran JM;Hunt JA;Richardson SM;Swift J;Wong LS
• 通讯作者: Wong LS