Optical approaches to delineate novel signalling pathways in skin blistering disease
Lead Research Organisation:
King's College London
Department Name: Randall Div of Cell and Molecular Biophy
Abstract
Recent advances in next generation sequencing have led to new insights into disease biology as well as opportunities for translational research. Through exome sequencing, we recently identified the first homozygous loss of function mutation in epidermal growth factor receptor (EGFR) in patients with inflammatory skin blistering. The EGFR signalling pathway regulates fundamental processes in cells including survival, migration, proliferation and secretion, in part through crosstalk with the integrin family of adhesion receptors. However, the mechanisms that control this crosstalk are largely unknown. This project will build on our novel findings to test the hypothesis that a balance between EGFR and integrin signalling plays a key role in maintaining skin homeostasis. Skin is a complex 3D tissue and analyzing contributions to tissue integrity from different endogenous cell populations is not possible without genetic manipulation. The use of 'caged' compounds, that are inert under native conditions but photolytically activated on exposure to certain light wavelengths, provides an excellent opportunity to manipulate endogenous protein behaviour within specific subsets of cells and study their role in tissue-like models. Chemical caging is a potentially powerful tool for translational research, but has been applied to a very limited subset of compounds/targets to date. We have established a collaboration with Tocris to develop selective optically-activated compounds to investigate the crosstalk between EGFR and integrin signaling within epidermal and stromal compartments of dermal equivalent 3D in vitro models. This project will provide excellent multidisciplinary training in translational cell biology and biological chemistry approaches to study mechanisms that control maintenance of human skin. Data arising from this study will provide important new tools for future studies of receptor signaling, as well as providing novel insight into fundamental regulatory pathways leading to human skin blistering diseases.
Publications
Hight-Warburton W
(2021)
a4/a9 Integrins Coordinate Epithelial Cell Migration Through Local Suppression of MAP Kinase Signaling Pathways.
in Frontiers in cell and developmental biology
Hight-Warburton W
(2019)
Regulation of cell migration by a4 and a9 integrins.
in The Biochemical journal
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
MR/N017242/1 | 30/09/2016 | 29/03/2021 | |||
1808965 | Studentship | MR/N017242/1 | 30/09/2016 | 29/03/2021 | Willow Hight-Warburton |
Description | ASCB Travel Award |
Amount | $975 (USD) |
Organisation | European Molecular Biology Organisation |
Sector | Charity/Non Profit |
Country | Germany |
Start | 12/2018 |
End | 12/2018 |
Description | Honor Fell Travel Award |
Amount | £450 (GBP) |
Organisation | Biochemical Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 12/2018 |
End | 12/2018 |
Description | RMS Travel Award |
Amount | £125 (GBP) |
Organisation | Royal Microscopy Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2017 |
End | 09/2017 |
Description | Actin 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Presented work to other academics - Had interesting discussions and questions |
Year(s) Of Engagement Activity | 2019,2020 |
Description | King's STARS workshop |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Fifteen year12 science students from schools that have a poor record of student progression to Universities for a one-week intensive lab-based work experience on the Guys campus at King's. Our students will be selected by our collaborating charity partner ACCESS, who work to provide work placements for talented school children from less privileged backgrounds. We want to inspire, enthuse and raise the ambitions of these students and encourage them to pursue biomedical research in future. |
Year(s) Of Engagement Activity | 2017,2019 |
Description | London Cell Motility Club |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Other audiences |
Results and Impact | Presented work to labs based in the London region. Received helpful critique of work. |
Year(s) Of Engagement Activity | 2019 |
Description | Tocris "Learn at lunch" |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Industry/Business |
Results and Impact | Industry experts gained better understanding of how their products are applied to answer scientific questions. Influence the kind of products they produce and future directions of product pipeline. |
Year(s) Of Engagement Activity | 2019 |