Link between barrier function and mechanical stress

Project ID: 2531ad1547

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UCL Lead department: London Centre for Nanotechnology (LCN)

Project Summary:

We propose to investigate the role of mechanics in diseases affecting monolayered epithelia. Epithelial monolayers are amongst the simplest tissues in the body, yet they act as essential barriers between the internal and external environment. One challenge to this barrier function is the mechanical stress that monolayers experience as part of their physiological function. For example, the lung epithelium stretches as we breathe and the intestinal epithelia deform during bowel movements. Therefore, to resist rupture and preserve barrier integrity, epithelia must adapt to their environment by finely adjusting their mechanical properties. At the molecular level, the mechanics of epithelia are governed by the cytoskeleton and the adhesive proteins that link cells to integrate them into a tissue-scale mechanical syncytium. This organisation leads to complex emergent rheological behaviours.

Disease and mutations can prevent establishment of appropriate tissue mechanical properties, leading to septicaemia and haemorrhage in adult tissues. For example, mutations in cytoskeletal and adhesive proteins lead to diseases presenting frequent fractures in the tissue, suggesting the epithelia have become fragilised. Other diseases (such as cancer and inflammatory bowel disease) lead to profound changes in gene transcription that affect cytoskeletal and adhesive proteins, likely impacting tissue mechanics. While it is recognized that pathologies affect epithelial mechanics, a lack of understanding of the exact nature of the mechanical changes induced and how these contribute to disease aetiology prevents the development of appropriate treatment strategies.

This project will investigate the link between epithelial mechanics and barrier integrity in health and disease. For this, we will develop methods to characterise tissue mechanics and barrier integrity across all relevant time- and length-scales. Using computational simulations, we will determine how the properties and organisation of the cytoskeleton and adhesions combine across scales to control tissue rheology, rupture properties, and barrier integrity in epithelia.