Orchestration of adhesion signalling by the mechanosensors talin and vinculin.

通过机械传感器 talin 和 vinculin 协调粘附信号。

基本信息

批准号：
BB/P000681/1
负责人：
Christoph Ballestrem
金额：
$ 55.45万
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：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FP000681%2F1
关键词：
Orchestration adhesion signalling mechanosensors talin

项目摘要

Cells continuously sense and produce their surrounding environment, which consists of fibrillar material the cells can attach to and is called extracellular matrix (ECM). Cell-ECM communication is particularly important during development or regeneration processes that require specific cellular responses to changing environments. Cellular responses comprise changes in motile behaviour (e.g. closing of wounds), contractility (e.g. functioning of the cardiovascular system) but also active remodelling of their ECM for the purpose of formation of new functional tissue. Many studies have focused on how cells sense their environment, but we are still far from understanding the mechanisms how cells perceive environmental signals and how they are translated into signals within cells that promote specific cellular responses.The environment of cells alters enormously during development, normal ageing, injury and certain diseases. For example, the mechanical properties of the ECM is thought to influence tumour progression and increased breast matrix stiffness is associated with poor survival. Stiffening of ECM also causes cardiovascular malfunctioning. Intriguingly cells contribute to the production of specific matrix on one hand but also respond to this produced environment on the other hand. Therefore, understanding how cells sense and produce their ECM environment is critically important if we want to get a step closer to treating the roots of diseases and promote regeneration.Cells can feel or sense their environment by exerting forces on it and probing its deformation. To transmit forces, they 'grab' neighbouring structures using surface 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 published a number of manuscripts showing that two of these coupling proteins, called talin and vinculin, are central to sensing of environmental changes. They are particularly important to measure the stiffness of their environment, they control cell migration, as well as cell growth and differentiation. In this proposal we also present important pilot data demonstrating that vinculin is critical for ECM remodelling. However how they do this is still unclear. In order to investigate how these proteins regulate the response to their environment, and to what extent they are involved in telling cells how to behave, the two laboratories in the prestigious Cell-Matrix Centre at the University of Manchester will team up and combine their long-standing expertise with the field of integrins signalling and cell-matrix interactions. The proposed research aims to to (i) understand the role of mechanical signals in the activation of talin and vinculin, (ii) how this activation helps vinculin and talin to associate with a large number other proteins that serve to exert specific signals (e.g. cell migration or cell growth) (iii) how vinculin with the newly found association of another protein called tensin is contributing to the formation and remodelling of ECM environment. To reach our goals, we will not only use cutting edge microscopy, biochemisty and molecular biology techniques but also a newly generated intracellular system whereby we can target proteins to specific compartments (mitochondria) in the cells which enable us to visualise and probe molecular interactions and behaviour under defined conditions. Our results will be combined into a model that outlines and potentially predicts how cells interpret and remodel their environment. Ultimately, the knowledge gained may lead to important changes in how we currently envisage environmental changes and their contribution to diseases. This may also lead to changes in treatment of patients, and it might thus, for example, contribute to improvements in disease prevention and in regeneration processes.

细胞连续感知并产生其周围环境，这些环境由细胞可以附着并称为细胞外基质（ECM）组成。细胞ECM通信在开发或需要特定细胞对变化环境的特定蜂窝响应的再生过程中尤为重要。细胞反应包括运动行为的变化（例如伤口关闭），收缩力（例如，心血管系统的功能），以及其ECM的主动重塑，以形成新的功能组织。许多研究都集中在细胞如何感知环境上，但是我们仍然远非了解细胞如何感知环境信号以及如何将它们转化为促进特定细胞反应的细胞中的信号。在发育过程中，细胞的环境在发育过程中大大改变，正常衰老，伤害和某些疾病。例如，ECM的机械性能被认为会影响肿瘤进展，并且乳腺基质刚度增加与存活不良有关。 ECM的僵硬还会引起心血管故障。有趣的细胞一方面有助于产生特定基质，但另一方面也响应了这种产生的环境。因此，如果我们想更接近治疗疾病根源并促进再生，那么了解细胞的感知和产生其ECM环境至关重要。细胞可以通过在其上施加力并探测其变形来感受到或感知其环境。为了传输力，他们使用表面蛋白来“抓住”相邻的结构，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。我们发表了许多手稿，表明这些耦合蛋白中的两个（称为塔林和vinculin）对于感知环境变化至关重要。它们对于测量环境的刚度，控制细胞迁移以及细胞生长和分化尤为重要。在此提案中，我们还提供了重要的试点数据，表明Vinculin对于ECM重塑至关重要。但是，他们如何做到这一点仍然不清楚。为了调查这些蛋白质如何调节对环境的反应，以及他们在何种程度上告诉细胞如何表现，曼彻斯特大学著名的细胞 - 马trix中心中的两个实验室将组合并结合长时间 - 具有整合素信号传导和细胞基质相互作用领域的专业知识。拟议的研究旨在（i）了解机械信号在塔林和vinculin激活中的作用，（ii）这种激活如何帮助vinculin和talin与大量其他蛋白质相关联，这些蛋白质用于发挥特定的信号（例如，细胞（例如）迁移或细胞生长）（iii）vinculin与另一种称为tensin的另一种蛋白质的新发现相关性如何有助于ECM环境的形成和重塑。为了实现我们的目标，我们不仅将使用尖端显微镜，生化和分子生物学技术，而且还将使用新生成的细胞内系统，我们可以将蛋白靶向细胞中的特定隔室（线粒体），从而使我们能够可视化和探测分子相互作用，以及分子相互作用以及探测分子的相互作用以及探测在定义条件下的行为。我们的结果将合并为概述并有可能预测细胞如何解释和重塑其环境的模型。最终，获得的知识可能会导致我们目前设想环境变化及其对疾病的贡献的重要变化。这也可能导致患者治疗的变化，因此，例如，这可能有助于改善疾病预防和再生过程。