Regulation of epithelial and endothelial cell-cell junctions by mechanical forces

通过机械力调节上皮和内皮细胞-细胞连接

• 批准号: BB/V003518/1
• 负责人: Anne Ridley
• 金额: $ 451.65万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV003518%2F1
• 关键词: Regulation; epithelial; endothelial; cell; junctions

Most parts of our body are constantly changing in response to mechanical forces. For example, every time we breathe in, our lungs expand. Our gut muscles contract to push food through the gut after we eat. When we move our arms or legs, our skin needs to stretch or compress. Our blood vessels are exposed to pulsatile blood flow generated by our hearts. Our lungs, gut and skin are lined by cells called epithelial cells, which provide the interface between the external environment and our body. Epithelial cells need to act as barriers: our skin, lung and gut epithelial cells protect us from bacteria and viruses, as well as toxic substances. Our blood vessels are lined by cells called endothelial cells, which mediate the transport of nutrients out of the blood stream to supply all our tissues and organs. They also allow Endothelial cells also need to form a barrier to stop the content of the blood leaking out into our tissues, yet still allow white blood cells into the tissues to fight infections and repair wounds. Epithelial cells and endothelial cells are normally tightly attached to each other to make a sealed barrier, similar to Velcro. Despite all the rapidly changing mechanical forces that epithelial cells and endothelial cells are constantly exposed to, it is important that they are flexible enough to move yet maintain their barrier functions. In addition, as a baby gradually grows into an adult, these cells need to divide yet still form tight barriers. Furthermore, if they are exposed to a sustained change in mechanical force, such as an increase in blood pressure, the cells need to adapt to this change.In our research, we aim to find out how epithelial cells and endothelial cells adapt to changes in mechanical forces. We will focus on studying how neighbouring epithelial or endothelial cells pass on messages about mechanical force to each other through their Velcro-like attachments. These attachments between cells contain thousands of different types of molecules. We will test which of these molecules are important for detecting messages from neighbouring cells, and how these molecules adapt to rapid changes in mechanical forces. We will also determine how cells respond to long-term changes to the level of mechanical forces, perhaps by altering the composition of their Velcro-like attachments to make them stronger or weaker.Epithelial cells and endothelial cells experience different kinds of mechanical forces because of their different locations in our bodies. We will directly compare the molecules that are required for sensing mechanical forces in these two types of cells. This will provide new insight into how cells adapt to their environment and the stresses that they experience. Through our work, we will generate important information about how our body forms and maintains barriers to the outside world, via epithelial cells, and between the blood and tissues, via endothelial cells. This will be useful to develop new ways to repair or replace damaged tissues, for example after operations, extensive wounding or severe infections.

我们身体的大部分部位都在不断地变化，以响应机械力。例如，每当我们吸气时，我们的肺就会扩张。我们的肠道肌肉收缩，以推动食物通过肠道后，我们吃。当我们移动手臂或腿时，我们的皮肤需要拉伸或压缩。我们的血管暴露于心脏产生的脉动血流。我们的肺，肠道和皮肤由称为上皮细胞的细胞组成，这些细胞提供了外部环境和我们身体之间的界面。上皮细胞需要充当屏障：我们的皮肤，肺和肠道上皮细胞保护我们免受细菌和病毒以及有毒物质的侵害。我们的血管由称为内皮细胞的细胞排列，这些细胞介导营养物质从血流中运输出来，以供应我们所有的组织和器官。他们还允许内皮细胞也需要形成一个屏障，以阻止血液的内容泄漏到我们的组织，但仍然允许白色血细胞进入组织，以对抗感染和修复伤口。上皮细胞和内皮细胞通常紧密地相互附着以形成密封屏障，类似于维可牢尼龙搭扣。尽管上皮细胞和内皮细胞不断暴露于所有快速变化的机械力，但重要的是它们足够灵活以移动，同时保持其屏障功能。此外，随着婴儿逐渐长大成人，这些细胞需要分裂，但仍然形成紧密的屏障。此外，如果细胞受到持续的机械力变化，例如血压升高，细胞需要适应这种变化。我们的研究旨在了解上皮细胞和内皮细胞如何适应机械力的变化。我们将专注于研究相邻的上皮或内皮细胞如何通过其Velcro样附件相互传递机械力的信息。细胞之间的这些附着物包含数千种不同类型的分子。我们将测试这些分子中哪些对于检测来自邻近细胞的信息很重要，以及这些分子如何适应机械力的快速变化。我们还将确定细胞如何对机械力水平的长期变化做出反应，可能是通过改变它们的Velcro样附着物的组成来使它们更强或更弱。上皮细胞和内皮细胞由于它们在我们体内的位置不同而经历不同类型的机械力。我们将直接比较这两种细胞中感知机械力所需的分子。这将为细胞如何适应环境和它们所经历的压力提供新的见解。通过我们的工作，我们将产生关于我们的身体如何形成和维持屏障到外部世界的重要信息，通过上皮细胞，血液和组织之间，通过内皮细胞。这将有助于开发修复或替换受损组织的新方法，例如在手术、大面积创伤或严重感染后。

项目成果

Rupture Strength of Living Cell Monolayers

活细胞单层的断裂强度

• DOI: 10.1101/2023.01.05.522736
• 发表时间: 2023
• 作者: Duque J

RhoU forms homo-oligomers to regulate cellular responses

RhoU 形成同源寡聚物来调节细胞反应

• DOI: 10.1242/jcs.261645
• 发表时间: 2024
• 期刊: Journal of Cell Science
• 影响因子: 4
• 作者: Clayton N

Analyzing the Roles of Rho GTPases in Cancer Cell Adhesion to Endothelial Cells Under Flow Conditions.

分析流动条件下 Rho GTP 酶在癌细胞粘附内皮细胞中的作用。

• DOI: 10.1007/978-1-0716-1350-4_7
• 发表时间: 2021
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Cerutti C

Bronchoconstriction damages airway epithelia by excess crowding-induced extrusion

过度拥挤引起的挤压会导致支气管收缩损伤气道上皮

• DOI: 10.1101/2023.08.04.551943
• 发表时间: 2023
• 作者: Bagley D

Removal of Stomatin, a Membrane-Associated Cell Division Protein, Results in Specific Cellular Lipid Changes.

• DOI: 10.1021/jacs.2c07907
• 发表时间: 2022-10-05
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Dona, Federico;Ozbalci, Cagakan;Paquola, Andrea;Ferrentino, Federica;Terry, Stephen J.;Storck, Elisabeth M.;Wang, Gaoge;Eggert, Ulrike S.
• 通讯作者: Eggert, Ulrike S.