Orchestration of adhesion signalling networks by the tensins and their impact in cell motility and matrix remodelling.

我们体内的组织由纤维状物质和活细胞组成的网状结构。细胞持续感知并产生这种纤维状物质，即所谓的细胞外基质（ECM），它包围着细胞并可以附着在细胞上。细胞-ECM通信在再生过程中特别重要，再生过程需要特定的细胞响应变化的ECM环境。细胞反应包括运动行为的变化（例如伤口闭合）以及形成新功能组织时ECM的主动重组。许多研究都集中在细胞如何检测（感知）环境信号，但我们仍然远远没有理解这些信号如何转化为促进特定细胞反应的信号。细胞的细胞外环境发生了巨大变化，特别是在衰老，损伤和某些疾病期间。例如，ECM的机械性质影响肿瘤进展，并且ECM的硬化导致纤维化（过量的基质产生），这反过来又可能导致受影响组织的功能障碍。有趣的是，细胞产生并同时响应这些环境变化。如果我们想更进一步治疗疾病的根源并促进再生，了解这一过程至关重要。细胞通过使用称为整合素的表面蛋白质抓住和拉动邻近的细胞外纤维材料来感知它们的环境。这些整合素不仅与细胞的环境结合，而且还连接到细胞内的骨架（细胞骨架）。这种联系不是直接的，而是由耦合两者的组件调节的。我们发表了大量的手稿，表明其中两种耦合蛋白，称为talin和vinculin，是感知环境变化的核心。它们对于测量其周围环境的硬度特别重要，并且它们控制细胞迁移。在这项提案中，我们提出了重要的试点数据表明，张力蛋白家族的成员，这是ECM重组的关键，与各种粘附调节蛋白，包括塔林和黏着斑蛋白相互作用。这些相互作用是如何介导的，以及不同的张力蛋白家族成员是如何与更广泛的蛋白质网络连接的，这些蛋白质网络将整合素偶联到细胞骨架上，目前还不清楚。此外，这些不同的相互作用如何影响细胞行为和基质重塑是未知的。我们将利用整合素介导的细胞-基质相互作用领域的长期专业知识，结合Ballestrem实验室建立的强大的新方法来解决这个问题。 拟议的研究目标是：（i）确定张力蛋白的关键相互作用伙伴;（ii）确定张力蛋白及其结合伙伴之间的相互作用是如何调节的，以及它们如何促进张力蛋白向细胞基质粘附位点的募集;（iii）研究张力蛋白及其相互作用伙伴如何促进ECM重塑和细胞运动。为了实现我们的目标，我们将采用尖端显微镜，生物化学和分子生物学技术的跨学科方法，旨在更好地了解功能组织生成的基本机制。最终，所获得的知识可能会导致开发新的方法来预防疾病（例如癌症，纤维化）和促进再生（伤口愈合）。

Tissues in our body consist of a meshwork of fibrillar material and living cells. The cells continuously sense and produce this fibrillar material, the so-called extracellular matrix (ECM), which surrounds the cells and to which they can attach to. Cell-ECM communication is particularly important during regeneration processes that require specific cellular responses to changing ECM environments. Cellular responses include changes in motile behaviour (e.g. closing of wounds) and also active reorganisation of their ECM when forming new functional tissue. Many studies have focused on how cells detect (sense) environmental signals, but we are still far from understanding how these are translated into signals that promote specific cellular responses.The extracellular environment of cells alters enormously particularly during ageing, injury and certain diseases. For example, the mechanical properties of the ECM influences tumour progression, and stiffening of ECM causes fibrosis (excess of matrix production), which in turn can lead to malfunctioning of the affected tissues. Intriguingly, cells produce and simultaneously respond to these environmental changes. Understanding this process is critically important if we want to get a step closer to treating the roots of diseases and promote regeneration. Cells sense their environment by grabbing and pulling the neighbouring extracellular fibrillar material using surface proteins called integrins. These integrins not only bind to the environment of the cells but also connect to a skeleton inside the cells (cytoskeleton). This link is not direct but is regulated by components that couple the two. We published a number of manuscripts showing that two of these coupling proteins, called talin and vinculin, are central to sensing environmental changes. They are particularly important for measuring the stiffness of their surroundings and they control cell migration. In this proposal we present important pilot data demonstrating that members of the tensin protein family, which are critical for ECM reorganisation, interact with a variety of adhesion regulatory proteins including talin and vinculin. How these interactions are mediated, and how different tensin family members are linked to the wider network of proteins that couple integrins to the cytoskeleton, is unclear. Additionally, how these different interactions influence cell behaviour and matrix remodelling is unknown. We will address this problem using long-standing expertise in the fields of integrin mediated cell-matrix interactions in combination with the powerful novel methods established in the Ballestrem laboratory. The proposed research aims are: (i) to identify key interaction partners of tensin; (ii) to determine how interactions between tensin and its binding partners are regulated and how they contribute to tensin recruitment to cell-matrix adhesion sites; (iii) to investigate how tensins, together with their interaction partners, contribute ECM remodelling and cell motility. To reach our goals, we will an interdisciplinary approach of cutting edge microscopy, biochemisty and molecular biology techniques with the aim to gain a better understanding of mechanisms that are fundamental for the generation of functional tissues. Ultimately, the knowledge gained may lead to the development of new way to prevent diseases (e.g. cancer, fibrosis) and promote regeneration (wound healing).