Project ID CM-HD2023_36

ThemeCM-HD

Co Supervisor 1A Randall Centre/BMBSWebsite

Co Supervisor 1B Peter Gorer Dept/SIMSWebsite

Defining mechano-signalling pathways in lung inflammation

Asthma is a major health problem affecting millions of people globally. This disease is characterised by acute or chronic lung inflammation, epithelial cell activation and tissue remodelling/fibrosis. Immune cells trigger changes in the lung epithelium leading to loss of barrier function, activation of tissue-resident fibroblasts and perpetuation of a ‘pro-fibrotic’ environment. However, the feedback loops between changing tissue biomechanics and epithelial/fibroblast activation remain unclear. We have recently discovered that cell-cell adhesion receptors in the lung epithelium play a key role in this process through dual roles in sensing of immune cells and changes to the mechanical properties of the surrounding matrix, leading to exacerbation of inflammation and tissue remodelling. The goal of this project is to analyse the mechanisms through which epithelial cells sense and respond to both inflammatory and biomechanical cues and how these translate into perpetuation of fibrosis or resolution/tissue regeneration. Advanced molecular biology, biochemical/proteomics and 3D culture/model approaches coupled with high resolution imaging will be used to address the following overarching aims:

Objectives:
1. Define novel mechano-responsive binding partners for epithelial cell adhesion receptors and the impact of inflammation and tissue stiffening on these interactions and downstream signalling (yrs1-2)
2. Determine roles for these mechano-signalling pathways in mediating barrier function, immune cell tissue infiltration and matrix organisation (yrs2-3)
3. identify how these signals impact tissue regeneration and lung homeostasis (yrs3-4).

Data arising from this project will provide novel insight into mechanisms driving inflammatory lung disease and identify potential targets for future therapeutic intervention.

One representative publication from each co-supervisor:

• Pfisterer K et al, FMNL2 regulates dynamics of fascin in filopodia. J Cell Biol. 2020. 219 (5): doi.org/10.1083/jcb.201906111

• Zanetti-Domingues et al, Architecture of EGFR basal complexes reveals autoinhibition mechanisms in dimers and oligomers. Nature Communications. 2018, 4325, doi.org/10.1038/s41467-018-06632-0