Understanding receptor-mediated mechanosensing and signalling in cell barrier function during tissue homeostasis and stress responses

Project description:
A fundamental challenge in biology is understanding how our cells sense, respond, and adapt to a variety of
microenvironmental stresses. Mechanisms of cellular adaptation are crucial for maintaining healthy tissue homeostasis,
as their failure undermines tissue fitness and contributes to age-related diseases such as chronic inflammation and
cancer.
The human gut is lined with epithelial cells that form a physical barrier between our bodies and the outside world. A key
challenge for these cells is how to maintain the integrity of this barrier in response to mechanical stress - the
biophysical cues such as stretch, compression and pressure that occur as food is pushed through our gut. In recent
years, mechanical forces have emerged as key regulators of cell behaviour through downstream activation of the
transcriptional co-regulators YAP/TAZ. However, the primary sensors of mechanical stresses upstream of YAP/TAZ
activation in this context remain poorly characterised.
An important way that cells sense and respond to changes in their environment is through G protein-coupled receptors
(GPCRs). We recently identified an orphan receptor (ligands currently unknown) that couples to YAP/TAZ activation in
intestinal epithelial cells during microenvironmental stress. However, what this receptor senses remains unknown.
Excitingly, newly acquired phosphoproteomics data suggest this receptor signals to proteins involved in cell-cell
junctions, extracellular matrix adhesion, and Rho GTPase activity. Since these pathways are known to be closely
interlinked and important in epithelial barrier function and mechanobiology, we hypothesise that this receptor is a
critical mechanosensor that controls barrier integrity in response to biophysical stress.
In a multidisciplinary research programme using cutting-edge techniques such as live-cell imaging, 3D organoid culture
and 2D mechanosensing models of the intestinal epithelium, you will investigate how receptor-mediated signalling
shapes normal intestinal homeostasis and epithelial barrier function in response to mechanical stress. Genetic loss of
function models will be generated using CRISPR-Cas9, which will be combined with integrative omics (RNAseq and
proteomics) for characterisation of receptor-mediate gene signatures. Training will be provided in omics and
bioinformatics as well as advanced cell biology techniques including organoid culture, IncuCyte imaging, confocal
microscopy, RNAi and CRISPR-Cas9. You will carry out your research in modern laboratories supported by cutting edge
microscopy and proteomics facilities. Understanding the role of this receptor in mechanosensing and barrier function
will pave the way for the identification of drug targets that could prevent the breakdown of healthy tissue homeostasis
and/or promote tissue regeneration in a number of disease contexts including inflammation and cancer.