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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.

上皮细胞是覆盖身体表面和内脏器官的细胞层。它们形成功能屏障，保护我们免受环境影响，并使我们的器官能够生成和维持不同成分的隔室，例如将视网膜与后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附复合物。其中一种粘附复合物称为紧密连接，在相邻细胞之间形成屏障；因此，紧密连接对于上皮细胞形成组织屏障至关重要，因为它们可以防止沿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，以防止上皮屏障破坏和组织衰竭。然而，上皮细胞经常受到物理压力，并在细胞分裂或器官和组织发育过程中经历细胞形状变化。因此，可能存在允许紧密连接适应不断变化的细胞形状的机制，并且可能帮助细胞感知和适应作用于紧密连接的外部物理力。在这里，我们重点关注这样的机制是否存在以及这样的分子桥是如何构建的问题。紧密连接由许多不同的蛋白质组成，形成一个分子网络，该网络从细胞表面的细胞间粘附蛋白开始，细胞通过该蛋白彼此相互作用。这些细胞间粘附蛋白与细胞内的大量蛋白质相互作用，调节各种连接功能，并被认为充当支持紧密连接结构的分子支架。其中一些蛋白质还可以与细胞骨架相互作用，细胞骨架是支持细胞结构和形状的蛋白质纤维网络。然而，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和内部细胞骨架的细胞间粘附蛋白相互作用的成分可能充当力转导连接体。因此，我们基于这种蛋白质构建了一种传感器，使我们能够确定该分子是否确实处于张力下。试点实验表明传感器功能正常，并且紧密连接确实是一种受力结构。我们现在的目标是确定连接结构原理，使紧密连接能够承受力并在细胞骨架和细胞表面之间进行传递，并利用功能测定来确定这些原理对上皮组织形成和发育的生理功能。预期结果将帮助我们了解与有机体发育、组织功能和再生相关的重要生理过程。它们将有助于我们了解破坏上皮组织的常见疾病，例如癌症、病毒和细菌感染，以及常见的慢性炎症和年龄相关疾病。我们还期望所发现的结果和原理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 drive trophoblast cell-cell fusion during placenta morphogenesis

ARHGEF18/p114RhoGEF 协调 PKA/CREB 信号传导和肌动球蛋白重塑，在胎盘形态发生过程中驱动滋养层细胞-细胞融合

DOI：
10.1101/2020.07.12.199141
发表时间：
2020
期刊：
影响因子：
0
作者：
Beal R
通讯作者：
Beal R

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

Rac1-PAK1 regulation of Rab11 cycling promotes junction destabilization.

RAC1-PAK1 RAB11循环的调节促进了连接处的稳定化。

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