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The University of Southampton
Biological Sciences

Research project: Defining the role of zeb1-dependent epithelial-mesenchymal crosstalk in lung fibrosis

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Idiopathic pulmonary fibrosis (IPF) is a life-threatening condition of the lungs where tissue becomes thickened, stiff, and scarred, limiting the amount of oxygen getting into the blood. The aim of this project is to provide effective targeted therapies for sufferers to reduce symptoms of this devastating disease and improve their quality of life as well as to identify biomarkers for IPF patients.

The contribution of epithelial-mesenchymal transition (EMT) to human fibrogenesis is controversial. EMT, a dynamic and reversible biological process by which epithelial cells lose their cell polarity and down-regulate cadherin-mediated cell-cell adhesion to gain migratory properties, is involved in embryonic development, wound healing, cancer and fibrosis. Although studies have clearly shown co-localisation of epithelial and mesenchymal markers in fibrotic disease, the number of fibroblasts arising from epithelial cells was small in some lineage tracing studies, and so any pathogenetic role for EMT in fibrosis has been uncertain. It was recently reported that rather than contributing directly to the mesenchymal population, ZEB1-dependent EMT of alveolar epithelial type II (ATII) cells contributes to fibrosis via aberrant epithelial-fibroblast crosstalk. In addition to facilitate TGFbeta-induced myofibroblast differentiation, unpublished data suggest that ZEB1-dependent paracrine signalling also drives the recruitment of lung fibroblasts. This proposal aims to map the global protein network changes in fibroblasts crosstalking with ATII cells undergoing EMT, and identify the paracrine factor(s) responsible for the fibroblast recruitment. Building on the preliminary data from the custom siRNA screen establishing STK11/LKB1 as a key regulator of ZEB1 expression, the consequences of its knockdown or activation in ATII cells, and the impact on epithelial-fibroblast crosstalk will be determined. I will use disease models involving the established RAS-induced EMT model in ATII cells, primary human ATII cells, and primary human lung fibroblasts from IPF patients or control donors together with proteomics profiling combined with bioinformatics. The findings will be important for elucidating the mechanisms controlling the ZEB1-dependent epithelial-mesenchymal crosstalk, and for understanding how fibrotic disease, including idiopathic pulmonary fibrosis (IPF), arises.

Funding provider: MRC

Funding dates: Oct 2019 – Sep 2022

Related research groups

Biomedical Sciences
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