Mechanotransduction at tight junctions and epithelial differentiation and dynamics

紧密连接处的力转导以及上皮分化和动力学

基本信息

批准号：
BB/N014855/1
负责人：
Karl Matter
金额：
$ 112.85万
依托单位：
University College London
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%2FN014855%2F1
关键词：
Mechanotransduction tight junctions epithelial differentiation

项目摘要

Epithelia are layers of cells that cover body surfaces and line internal organs. They form functional barriers that protect us from the environment and enable our organs to generate and maintain compartments of different compositions, such as the barrier that separates the retina from the blood at the back or the eye. For individual epithelial cells to interact and form epithelial tissues, they need to assemble adhesive complexes with neighbouring cells. One of these adhesive complexes is called tight junction and forms a barrier in between neighbouring cells; hence, tight junctions are essential for epithelia to form tissue barriers as they prevent random diffusion along the space in between neighbouring cells. Consequently, the integrity of tight junctions must be maintained in order to prevent epithelial barrier breakdown and tissue failure. However, epithelial cells are often under physical strain and undergo cell shape changes during cell division or during the development of our organs and tissues. Therefore, mechanisms are likely to exist that allow tight junctions to adapt to changing cell shapes and, possibly, help cells sense and adapt to external physical forces that act on tight junctions. Here, we focus on the questions of whether such mechanisms exist and how such molecular bridges are built. Tight junctions are composed of many different proteins that form a molecular network that starts with cell-cell adhesion proteins at the cell surface by which cells interact with each other. These cell-cell adhesion proteins interact with a large range of proteins inside the cells that regulate the various junctional functions and that are thought to function as molecular scaffolds that support the structure of tight junctions. Some of these proteins can also interact with the cytoskeleton, a network of protein fibres that supports the cell's structure and shape. However, the functional relevance of these interactions is not well understood. We hypothesized that components that can interact with the cell-cell adhesion proteins at the cell surface and the internal cytoskeleton might work as force transducing linkers. Hence, we have constructed a sensor based on such a protein that allows us to determine whether the molecule is indeed under tension. Pilot experiments indicate that the sensor is functional and that tight junctions are indeed a force-bearing structure. Our objectives now are to determine the junctional architectural principles that enable tight junctions to bear forces and transduce them between the cytoskeleton and the cell surface, and to make use of functional assays to determine the physiological function of these principles for epithelial tissue formation and development. The expected results will help us to understand physiologically important processes relevant for organism development, and tissue function and regeneration. They will contribute to our understanding of common diseases that disrupt epithelial tissues such as cancer, viral and bacterial infections, and common chronic inflammatory and age-related conditions. We also expect that the results and principles to be discovered will support tissue engineering and regenerative medicine approaches.

上皮是覆盖身体表面和线内器官的细胞层。它们形成功能性障碍，可以保护我们免受环境的影响，并使我们的器官能够生成和维护不同组合物的隔室，例如将视网膜与背部或眼睛的血液分开的屏障。为了使单个上皮细胞相互作用并形成上皮组织，它们需要与邻近细胞组装粘合剂复合物。这些粘合剂复合物之一称为紧密连接，并在相邻细胞之间形成障碍。因此，紧密连接对上皮形成组织屏障至关重要，因为它们可以防止沿着相邻细胞之间的空间随机扩散。因此，必须保持紧密连接的完整性，以防止上皮屏障崩溃和组织故障。但是，上皮细胞通常处于身体应变下，并且在细胞分裂期间或在我们的器官和组织的发展过程中会经历细胞形状的变化。因此，可能存在允许紧密连接的机制适应变化的细胞形状，并可能帮助细胞感知并适应对紧密连接的外部物理力。在这里，我们关注是否存在这种机制以及如何建立这种分子桥的问题。紧密连接由许多不同的蛋白质组成，这些蛋白质形成一个分子网络，该蛋白质是从细胞表面的细胞 - 细胞粘附蛋白开始的，细胞表面相互相互作用。这些细胞 - 细胞粘附蛋白与调节各种连接功能的细胞内的大量蛋白质相互作用，被认为是支持紧密连接结构的分子支架。这些蛋白质中的一些也可以与细胞骨架相互作用，这是一个支持细胞结构和形状的蛋白质纤维网络。但是，这些相互作用的功能相关性尚不清楚。我们假设可以与细胞表面的细胞细胞粘附蛋白相互作用，并且内部细胞骨架可能与力转导连接器相互作用。因此，我们基于这样的蛋白质构建了一个传感器，该传感器使我们能够确定该分子是否确实处于张力下。试验实验表明，传感器是功能性的，紧密连接确实是一种强力结构。我们现在的目标是确定连接架构原理，使紧密的连接可以承受力并在细胞骨架和细胞表面之间转导，并利用功能分析来确定上皮组织形成和发育的这些原理的生理功能。预期的结果将有助于我们了解与生物体开发以及组织功能和再生有关的生理重要过程。它们将有助于我们对破坏上皮组织（例如癌症，病毒和细菌感染）以及常见的慢性炎症和与年龄相关的常见组织的理解。我们还希望发现的结果和原则将支持组织工程和再生医学方法。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tight junctions.

连接紧密。

DOI：
10.1016/j.cub.2023.09.027
发表时间：
2023
期刊：
CB
影响因子：
0
作者：
Balda MS
通讯作者：
Balda MS

ZO-1 Guides Tight Junction Assembly and Epithelial Morphogenesis via Cytoskeletal Tension-Dependent and -Independent Functions.

DOI：
10.3390/cells11233775
发表时间：
2022-11-25
期刊：
Cells
影响因子：
6
作者：
通讯作者：

ARHGEF18/p114RhoGEF Coordinates PKA/CREB Signaling and Actomyosin Remodeling to Promote Trophoblast Cell-Cell Fusion During Placenta Morphogenesis.

DOI：
10.3389/fcell.2021.658006
发表时间：
2021
期刊：
Frontiers in cell and developmental biology
影响因子：
5.5
作者：
Beal R;Alonso-Carriazo Fernandez A;Grammatopoulos DK;Matter K;Balda MS
通讯作者：
Balda MS

Reciprocal regulation between cell mechanics and ZO-1 guides tight junction assembly and epithelial morphogenesis

细胞力学和 ZO-1 之间的相互调节指导紧密连接组装和上皮形态发生

DOI：
10.1101/2022.07.17.500023
发表时间：
2022
期刊：
影响因子：
0
作者：
Haas A
通讯作者：
Haas A

Rac1-PAK1 regulation of Rab11 cycling promotes junction destabilization.

DOI：
10.1083/jcb.202002114
发表时间：
2021-06-07
期刊：
The Journal of cell biology
影响因子：
0
作者：
Erasmus JC;Smolarczyk K;Brezovjakova H;Mohd-Naim NF;Lozano E;Matter K;Braga VMM
通讯作者：
Braga VMM