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

10 25 50
publication icon
Hight-Warburton W (2019) Regulation of cell migration by a4 and a9 integrins. in The Biochemical journal

 
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 09/2017 
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